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]

Link to SEPIO compliant JSON-LD document

Variant: NM_005633.3(SOS1):c.1666G>A (p.Val556Ile)

CA346365661

561347 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 49e7cd7f-a099-4c39-b8b7-e1a01bbe79f8

HGVS expressions

NM_005633.3:c.1666G>A

NM_005633.3(SOS1):c.1666G>A (p.Val556Ile)

NC_000002.12:g.39022762C>T

CM000664.2:g.39022762C>T

NC_000002.11:g.39249903C>T

CM000664.1:g.39249903C>T

NC_000002.10:g.39103407C>T

NG_007530.1:g.102702G>A

ENST00000395038.6:c.1666G>A

ENST00000402219.6:c.1666G>A

ENST00000426016.5:c.1666G>A

Uncertain Significance

PP2

BS1 BP4 PS4 PM5 PM1 PM6

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1666G>A (p.Val556Ile) variant in SOS1 was present in 0.005437% (1/18392) of East Asian alleles in gnomAD v2.1.1 and was absent from v3. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 31219622; GeneDx internal data, SCV000808076.1; Invitae internal data; BC Children’s Hospital internal data). 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: PP2.

PP2

SOS1 is a missense-constrained gene.

BS1

Present in 0.005437% (1/18392) of East Asian alleles in gnomAD v2. Absent from v3.

BP4

REVEL score 0.362. Relatively highly conserved in mammals (no animals in UCSC database have Ile at this site, but the dolphin has Ser and several non-mammals have alternate amino acids here). Splicing is not predicted to be impacted.

PS4

This variant has been reported in 1 published case; however the EP did not think this variant was causing the proband's phenotype.

PM5

c.1668A>C (p.Val556=) has been reported as a VUS by Greenwood Genetic Center.

PM1

Does not occur between aa 420-500.

PM6

One published case is reported to be de novo, but the EP did not think this variant was causing the proband's phenotype.

PubMed:31219622

Approved on: 2020-03-09

Published on: 2020-03-09

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