Table 4 Presumptive loss of function variants in known disease-related genes that are not disease-causingâ€
Gene | Variant | Zygosity | Disease name | Phenotype-specific OMIM ID | Reason to question pathogenicity | Proposed mechanism for non-pathogenicity |
|---|---|---|---|---|---|---|
COL8A2 | NM_005202.4:c.1815C>A;p.(Tyr605*) | Homozygous | Corneal dystrophy, Fuchs endothelial, 1 | 136800 | Updated high MAF | Pathogenicity is due to GOF rather than LOF59 |
DENND5A | NM_015213.4:c.3387+3G > T;r.3305_3387del;p.(Lys1102Thrfs*27) | Homozygous | Developmental and epileptic encephalopathy 49 | 617281 | Homozygous in an unaffected sibling | ?Resilience |
RPGR | NM_000328.3:c.1905+1 G > A | Hemizygous | Cone-rod dystrophy, X-linked, 1 | 304020 | Homozygous in healthy individuals | The variant is a missense variant in the canonical transcript while +1 in all others |
LIPN | NM_001102469.2:c.302delG;p.(Gly101Glufs*7) | Homozygous | Ichthyosis, congenital, autosomal recessive 8 | 613943 | Homozygous in an unaffected sibling | Gene-disease assertion in OMIM is based on one family |
IQSEC1 | NM_001134382.3:c.2978del;p.(Pro993Hisfs*127) | Homozygous | Intellectual developmental disorder with short stature and behavioral abnormalities | 618687 | Homozygous in healthy individuals | The deleted bp is the last bp in the exon-intron boundary and the intron is only one base pair long |
NPHP4 | NM_015102.5:c.2818-2 T > A | Homozygous | Nephronophthisis 4 | 606966 | Updated high MAF | Previous study has shown that the aberrant transcripts do not cause frameshift truncation28 |
GNAT1 | NM_144499.3:c.858 C > G;p.(Tyr286*) | Homozygous | Night blindness, congenital stationery, type 1 G | 616389 | Homozygous in an unaffected father | Truncates ~20% of the protein where no deleterious variants are reported |
OFD1 | NM_003611.3:c.2600-1 G > C | Hemizygous | Orofaciodigital syndrome I | 311200 | Hemizygous in an unaffected father | The variant is not a LOF variant (does not cause a frameshift truncation) |
EVC | NM_001306090.2:c.2731 C > T,p.(Arg911*) | Homozygous | Ellis-van Creveld syndrome | 225500 | Updated high MAF | Truncates ~9% of the protein |
GUCA1A | NM_001384910.1:c.235delC,p.(Ala79Glyfs*23) | Homozygous | Cone dystrophy-3 | 602093 | Homozygous in healthy individuals | Pathogenicity is due to GOF rather than LOF60 |
MKS1 | Exon 1 loss at the RNA level | Homozygous | Bardet-Biedl syndrome 13 | 615990 | Alternative etiology was identified | Technical error |
LETM1 | NM_012318.3:c.1678A>T;p.(Lys560*) | Homozygous | Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction | 620089 | Homozygous in an unaffected sibling | ?Resilience |
LZTFL1 | NM_001276379.1:c.3 G > A;p.? | Homozygous | Bardet-Biedl syndrome 17 | 615994 | Updated high MAF | Startloss in some transcript and UTR variant in others. GTEX database reported that the shorter transcripts (where the variant is located in the UTR regions) are the ones abundantly expressed in most tissues especially the brain and reproductive organs |
PDE11A | NM_016953.3:c.1633C>T;p.(Arg545*) | Homozygous | Pigmented nodular adrenocortical disease, primary, 2 | 610475 | Homozygous in an unaffected sibling | Pathogenicity is due to GOF rather than LOF61 |
RP1L1 | NM_178857.6:c.5959 C > T;p.(Gln1987*) | Homozygous | Retinitis pigmentosa 88 | 618826 | Updated high MAF | Truncates a small part of the C-terminus where no deleterious variants are reported |
CDKL5 | NM_003159.2:c.2854 C > T;p.(Arg952*) | Heterozygous | Developmental and epileptic encephalopathy 2 | 300672 | Updated high MAF | Truncates 7.7% of the protein |
