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.1645A>G (p.Thr549Ala)

CA346365698

561935 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 421d6e49-e013-40c6-b4d6-29c628949bf1

HGVS expressions

NM_005633.3:c.1645A>G

NM_005633.3(SOS1):c.1645A>G (p.Thr549Ala)

NC_000002.12:g.39022783T>C

CM000664.2:g.39022783T>C

NC_000002.11:g.39249924T>C

CM000664.1:g.39249924T>C

NC_000002.10:g.39103428T>C

NG_007530.1:g.102681A>G

ENST00000395038.6:c.1645A>G

ENST00000402219.6:c.1645A>G

ENST00000426016.5:c.1645A>G

Uncertain Significance

PP2 PM2

PS4 PP3 PM1 PM5

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1645A>G (p.Thr549Ala) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PM2, PP2.

PP2

SOS1 is a missense-constrained gene.

PM2

Absent from both versions of gnomAD.

PS4

Seen in 1 proband at GeneDx without a diagnosis of a RASopathy.

PP3

REVEL score 0.589. 1 animal in the UCSC database (coelacanth) has A at this site; all others have T. Splicing is not predicted to be impacted.

PM1

Does not fall between aa 420-500.

PM5

Only 1 other variant in this codon in ClinVar (c.1646C>A (p.Thr549Lys), VUS as classified by EP).

Approved on: 2020-03-19

Published on: 2020-03-23

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