Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_005633.3(SOS1):c.1276C>A (p.Gln426Lys)

CA346366546

561622 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 647d7dfd-d843-4710-bfaa-f9e90a528d2f

Approved on: 2020-07-27

Published on: 2020-07-27

HGVS expressions

NM_005633.3:c.1276C>A

NM_005633.3(SOS1):c.1276C>A (p.Gln426Lys)

ENST00000395038.6:c.1276C>A

ENST00000402219.6:c.1276C>A

ENST00000426016.5:c.1276C>A

ENST00000472480.1:n.120C>A

NC_000002.12:g.39023152G>T

CM000664.2:g.39023152G>T

NC_000002.11:g.39250293G>T

CM000664.1:g.39250293G>T

NC_000002.10:g.39103797G>T

NG_007530.1:g.102312C>A

Likely Pathogenic

PM2 PM1 PS4_Supporting PP2 PP3

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1276C>A (p.Gln426Lys) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 1 individual with a diagnosis of Noonan syndrome (PS4_Supporting; GeneDx internal data, ClinVar SCV000808402.1). SOS1 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln426Lys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2, PP3, PS4_Supporting.

PM2

Absent from both versions of gnomAD.

PM1

The RASopathy EP has defined amino acids 420-500 of SOS1 to be a region supporting pathogenicity.

PubMed:29493581

PS4_Supporting

Identified in 1 proband with a diagnosis of Noonan syndrome.

PP2

The RASopathy EP has defined SOS1 to be a missense-constrained gene where pathogenic missense variants are common (PMID: 29493581).

PP3

REVEL 0.786. Entirely conserved in UCSC database. Not predicted to impact splicing.

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