Table 4 Summary of discordant laboratory and clinician interpretations.

From: Challenges in genetic testing: clinician variant interpretation processes and the impact on clinical care

IDa

Overall laboratory interpretation of testingb

Variant(s) of interest

Laboratory variant classificationc

Inheritance pattern

Overall clinician interpretation of testingd

Clinician interpretation description

Clinician interpretation support

Impact on care

MG-17

Nondiagnostic

GDF1 (NM_001492.6): c.382A>C (p.T128P)

VUS

AD

Likely diagnostic

Based on XXX’s history and our limited information on this gene, we feel that this is the most likely explanation for her cardiac disease.

Phenotype, gene pathway

Recurrence risk

MG-18

Nondiagnostic

RPL8 (NM_000973.3): c.113A>G (p.H38R)

VUS

AD

Likely diagnostic

While the significance of this variant is unclear, it appears to have appeared de novo (new) in XXX, which makes it more likely to be clinically significant. Additionally, XXX’s clinical presentation, while not classic, could be consistent with Diamond–Blackfan anemia.

Inheritance, phenotype, gene pathway

Surveillance, recurrence risk

MG-38

Nondiagnostic

1. MEGF8 (NM_001410.3): c.3810G>A (p.Thr1270=)

1. VUS

AR

Likely diagnostic

In analysis of the two MEGF8 changes, the maternally inherited variant seems more likely to affect splicing and be disease-causing, although we cannot be certain without functional studies. The paternally inherited variant is more difficult to determine if it is disease-causing or benign. The combination of these two variants is challenging to interpret, given these limitations. Dr. XXX feels XXX has a likely diagnosis of Carpenter syndrome at this time.

Genotype, phenotype

Recurrence risk

2. MEGF8 (NM_001410.3): c.7573G>A (p.V2525M)

2. VUS

MG-39

Diagnostic

EVC2 (NM_147127.5): c.3194delA (p.Asp1065Valfs*14)

LP

AR/AD

Uncertain

We discussed that we had specifically noted that XXX had some teeth anomalies. Otherwise does not currently have features that have been associated with EVC2-related Weyers acrofacial dysostosis. XXX’s presentation would be atypical as he does not have nail or hand findings…at this point we do not have any clinical recommendations for XXX, but a referral to Orthopedics may be appropriate in the future if he is having skeletal concerns.

Phenotype

Recurrence risk, additional testing

OP-02

Nondiagnostic

ABCC8 (NM_000352.6): c.1886C>T (p.Pro629Leu)

VUS

AR/AD

Likely diagnostic

XXX is a XXX-old girl with variable blood sugars, including episodes of hypo-and hyperglycemia. Recent genetic testing has revealed mutations that may be causative.

Phenotype

Recurrence risk

OP-14

Nondiagnostic

1. NOD2 (NM_022162.3): c.566C>T (p.Thr189Met)

1. VUS

1. AD

Likely diagnostic

His specific variant has been reported with ulcerative colitis and NOD2-associated autoinflammatory disease, which is characterized by recurrent fevers, arthritis, dermatitis, and lower extremity edema. Discussed that the PLCG2 mutation has been reported with autoinflammation as well. Therefore, explained that these mutations are likely related to his recurrent fevers but can not verify this.

Phenotype

Recurrence risk, surveillance/management

2. PLCG2 (NM_002661.5): c.923C>T(p.Ala308Val)

2. VUS

2. AD

OP-23

Diagnostic

NFKB1 (NM_003998.4): c.1944dupC (p.Asn649Glufs*16)

LP

AD

Uncertain

Exome sequencing showed XXX to be heterozygous for the NFKB mutation which is associated/diagnostic with CVID. XXX has had an extensive workup consisting of immunoglobulin levels, flow cytometry, and vaccine titers (all grossly unremarkable).

Phenotype

Surveillance, recurrence risk

In later clinic note: XXX has been found to have a NKFB gene mutation that may be associated with CVID.

OP-27

Nondiagnostic

PTPN11 (NM_002834.5):c.223G>C (p.Ala75Pro)

VUS

AD

Likely diagnostic

At XXX’s last visit we pursued molecular genetic testing for Noonan syndrome which resulted with a heterozygous variant of unknown significant in the PTPN11 gene which as not clearly pathogenic or benign. Given clinical findings, I highly suspect this is a pathogenic variant representing a true diagnosis of Noonan syndrome.

Phenotype

Surveillance/management, recurrence risk

OP-33

Nondiagnostic

GRIN2A (NM_000833.5): c.2258G>C (p.Gly753Ala)

VUS

AD

Diagnostic

XXX is developmentally normal with history of focal epilepsy ie complex partial epilepsy with 2nd generalization and GRIN2A mutation. XXX is currently on 2 antiseizure medication and doing fair with occasional breakthrough seizures. NGS showed de novo GRIN2A (father testing not done).

Phenotype

Recurrence risk

OP-35

Nondiagnostic

ATP7B (NM_000053.4): c.2519C>T (p.Pro840Leu)

LP

AR

Diagnostic

XXX has had gene studies performed. XXX is heterozygous for ATP7B. With having elevated copper content in the liver, XXX would be considered a compound heterozygous with the other mutation for Wilson disease yet to be determined.

Phenotype, clinical diagnosis

Surveillance

OP-41

Nondiagnostic

SLC33A1 (NM_004733.4): c.1525G>A (p.Gly509Ser)

VUS

AR/AD

Likely diagnostic

XXX has a maternally inherited pathogenic mutation that could explain XXX clinical phenotype. Deletion/duplication analysis of this abnormality must be performed to definitively diagnose him with this condition.

Phenotype

Additional testing

OP-51

Nondiagnostic

TAF1 (NM_004606.5): c.893_895DupAGG (p.Gln298dup)

VUS

XLR

Likely diagnostic

Whole exon sequencing revealed two genetic abnormalities that may explain XXX phenotype…the more likely explanation for his condition. This is a mutation in the TAF1 gene. When mutated this can cause an X-linked intellectual disability syndrome.

Phenotype

Recurrence risk, management/medication

OP-53

Indeterminatee

TTN (NM_133378.4): c.17299delC (p.S5767X)

LP

AR/AD

Diagnostic

XXX has a congenital onset form of titin myopathy; a muscle biopsy would be required in order to further classify his condition. The family is not interested in pursuing a muscle biopsy at this time.

Phenotype

Surveillance (referral to cardiology), recurrence risk

OP-76

Nondiagnostic

1. DNAH11 (NM_001277115.2): c.6353G>A (p.Gly2118Asp)

1. VUS

AR

Diagnostic

XXX is a XXX-old female with genetic testing positive for primary ciliary dyskinesia (2 mutations for DNAH11). These two mutations above have not been extensively studied and so XXX’s phenotype is uncertain.

Phenotype

Recurrence risk, surveillance (deferred biopsy)

2. DNAH11 (NM_001277115.2): c.8620C>T (p.Leu2874Phe)

2. VUS

OP-81

Nondiagnostic

1. CASQ2 (NM_001232.4): c.923C>T(p.Pro308Leu)

1. P

AR

Diagnostic

Two mutations in CASQ2, indicating a recessive pattern of inheritance, fits well with the family history of two affected siblings and no additional affected relatives.

Genotype/phenotype

Recurrence risk, surveillance, additional familial testing

2. CASQ2 (NM_001232.4):c.446T>G(p.Ile149Ser)

2. VUS

OP-94

Diagnostic

DDX3X (NM_001193416.1): c.202_205dupGCGT (p.Tyr69Cysfs*3)

LP

XLR/XLD

Uncertain

Results of the next-generation sequencing were not conclusive…I am aware of the DDX3X finding, but the movement disorder would be better explained by the PNPLA6

Phenotype

Surveillance, recurrence risk

OP-96

Nondiagnostic

TRPM4 (NM_017636.4): c.2740A>T (p.Lys914*)

VUS

AD

Likely diagnostic

XXX is a young patient with a channelopathy, likely caused by the mutation listed above

Genotype/phenotype

Recurrence risk

OP-100

Indeterminate

MEFV (NM_000243.3): c.2080A>G (p.Met694Val)

P

AR/AD

Diagnostic

Many patients with confirmed FMF have either a homozygous mutation or 2 heterozygous mutations in MEFV but more than 30% of patients do not. Therefore, FMF should be a clinical diagnosis that is made based off of history, exam, ethnicity, and family history. Therefore, XXX has a presumed diagnosis of FMF.

Phenotype, clinical diagnosis

Management, recurrence risk

  1. AD autosomal dominant, AR autosomal recessive, CVID FMF NGSnext-generation sequencing, LP  likely pathogenic, P  pathogenic, VUS variant of uncertain significance, XLR  X-linked recessive, XLD X-linked dominant, CVID common variable immunodeficiency, FMF familial Mediterranean fever.
  2. aID numbers beginning with an MG were ordered by a medical geneticist and those starting with an OP were ordered by another specialty.
  3. bOverall laboratory interpretation of testing represents if the variant(s) and overall genotype reported were considered diagnostic overall, not a representation of the individual variant interpretation. Overall laboratory interpretation of “diagnostic” was assigned to reports where variant(s) were reported as consistent with a disease, “nondiagnostic” was assigned to reports where the lab indicated “no diagnostic genotype," “no pathogenic variants," or only one pathogenic variant for an autosomal recessive disease. Indeterminate was assigned when a single pathogenic or likely pathogenic variant was identified in a gene where the inheritance of the variant is unclear.
  4. cVariant classification by the laboratory was not evaluated for this study and reflects the interpretation from the report the date it was issued. It is possible variant interpretations have changed since testing was completed.
  5. dOverall clinician interpretation of testing reflects the interpretation conveyed to the patient as documented in the medical record and supported by the clinician interpretation description. “Diagnostic” was assigned when the clinician states with clarity that the result is causative of the patient phenotype, “likely diagnostic” was assigned when the clinician states that a result is likely causative of the patient phenotype but the language is not definitive, “uncertain” was assigned when a clinician’s documentation indicates that they are uncertain that a pathogenic or likely pathogenic variant is causative of the patient disease.
  6. eTTN also shows variable expressivity and genotypes associated with different disorders.
Back to article page