Table 1 Patients, variant classification and clinical features.

From: Expanding the clinical spectrum of COL2A1 related disorders by a mass like phenotype

Patient

Subject 1A

Subject 1B

Subject 2

Subject 3

Sex

Male

Female

Female

Male

Age at last examination

13 years

44 years

53 years

22 years

Family history

Positive: grandfather with arthritis/gout

Positive: father with arthritis/gout

Uncertain: father with suspected arthritis

Uncertain: parents n.a. for clinical examination

Variant classification

COL2A1 (NM_001844.5) variant (c. notation, p. notation)

c.3936G > T (het) p.(Lys1312Asn)

c.3936G > T (het) p.(Lys1312Asn)

c.193G > A (het) p.(Asp65Asn)

c.4013G > A (het) p.(Ser1338Asn)

gnomAD v.2.1.1

total population allele frequency (allele count/allele number/hom)

0.000003976 (1/251,478/0)

0.000003976 (1/251,478/0)

0 (0/280,928/0)

0 (0/251,496/0)

VarSome pathogenicity prediction (damaging/uncertain/tolerated)

13/1/2

13/1/2

11/1/4

3/2/11

HGMD/ClinVar

N.l./N.l.

N.l./N.l.

N.l./VUS*

N.l./N.l.

ACMG/AMP classification (Criteria)

LPV (PM1, PM2†, PP2, PP3)

LPV (PM1, PM2†, PP2, PP3)

LPV (PM1, PM2, PP2, PP3)

VUS (PM1, PM2, PP2, BP4)

Clinical features

Height

178 cm (+ 1.8 SD, > 95P)

172 cm (+ 1.3 SD, > 90P)

179 cm (+ 2.4 SD, > 95P)

198 cm (+ 3.0 SD, > 95P)

Tall stature

Yes

Yes

Yes

Yes

Arm span/arm span to height ratio

191 cm/1.07

185 cm/1.07

N.a.

N.a.

Arachnodactyly

Yes

Yes

Yes

Yes

Wrist and thumb sign

Both positive (SySc. 3)

Positve wrist sign (SySc. 1)

Both positive (SySc. 3)

Positive thumb sign (SySc. 1)

Dural ectasia

Yes (SySc. 2)

N.a.

Yes (SySc. 2)

Yes (SySc. 2)

Pectus deformity

P. excavatum (SySc. 1)

P. excavatum (SySc. 1)

No

P. carinatum (SySc. 2), Asymmetric thorax

Spinal deformity

Kyphosis (SySc. 1)

Kyphosis (SySc. 1)

Scoliosis (SySc. 1)

Scoliosis (SySc. 1)

Foot deformity

No

Pes planus (SySc. 1)

Pes planus (SySc. 1)

Hindfoot deformity (SySc. 2)

Aortopathy

No (ARD 29 mm, Z-score 1.3)

No (ARD 32 mm, Z-Score 0.4)

No (ARD 33 mm, Z-score 0.68)

No (ARD 36 mm, Z-Score 1.2)

Craniofacial features

High arched palate

Dolichocephaly, enophthalmus malar hypoplasia, high arched palate (SySc. 1)

No

Dolichocephaly, malar hypoplasia, retrognathia, high arched palate (SySc. 1)

Osteoarthritis

Yes

Yes

No

No

Other features

anterospondylolisthesis, vertebral osteochondrosis

bone odema of both feet

hypermobility of knee and elbow joints, varicosis

suspected bicuspid aortic valve, myopia (< 3dpt)

Diagnosis according to revised Ghent nosology

MASS-like (Systemic score 7)

MASS-like (Systemic score 5)

MASS-like (Systemic score 7)

MASS-like (Systemic score 9)

  1. Patients, variant classification and clinical features. Variant details and clinical features are listed by patient. Nucleotide numbering uses + 1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1. gnomAD, Genome Aggregation Database (v2.1.1); allele frequency in total population is given; allele count/allele number/hom, total number of alleles/total number of analysed alleles/number of homozygous carriers. HGMD, Human Gene Mutation Database. ClinVar, database on the relationships between human variations and phenotypes. Variants were classified as recommended by ACMG/AMP: VUS, variant of uncertain significance or with conflicting interpretations of pathogenicity; LPV, likely pathogenic variant. Clinical features supporting a MASS-like phenotype are shown in bold and the respective systemic score (SySc.) according to the revised Ghent nosology is given in parentheses12. het, heterozygous; N.a., not available; N.l., not listed; SD, standard deviation; ARD, aortic root diameter; MASS, Myopia, mitral valve prolapse, borderline and non-progressive aortic root dilatation, skeletal findings and striae.
  2. *, variant c.193G > A p.(Asp65Asn) has previously been reported in the ClinVar database and classified as VUS. The patient’s condition and the inheritance were not recorded.
  3. †, VarSome 10.2 assigns PM2 for dominant genes if the allele count of the variant is less than 5 in the gnomAD database (for details see Supplementary Results).
Back to article page