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.1385T>A (p.Phe462Tyr)

CA297267

40674 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9d7b1ff4-cd7d-433d-965c-949deabe01f4

Approved on: 2020-07-27

Published on: 2020-07-27

HGVS expressions

NM_005633.3:c.1385T>A

NM_005633.3(SOS1):c.1385T>A (p.Phe462Tyr)

ENST00000395038.6:c.1385T>A

ENST00000402219.6:c.1385T>A

ENST00000426016.5:c.1385T>A

ENST00000472480.1:n.229T>A

NC_000002.12:g.39023043A>T

CM000664.2:g.39023043A>T

NC_000002.11:g.39250184A>T

CM000664.1:g.39250184A>T

NC_000002.10:g.39103688A>T

NG_007530.1:g.102421T>A

Uncertain Significance

PM1 PP2 PP3

BS1 BS2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1385T>A (p.Phe462Tyr) variant in SOS1 was present in 0.002891% (1/34590) of Latino alleles in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been identified in at least 1 unaffected parent of a proband with features of a RASopathy; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000209112.10). 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.Phe462Tyr variant may impact the protein (PP3). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PP2, PP3.

PM1

The RASopathy EP has defined aa 420-500 of SOS1 to be a region supporting pathogenicity (PMID: 29493581).

PP2

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

PP3

REVEL 0.81. Entirely conserved in UCSC database. Alamut does not predict an impact to splicing.

BS1

Present in 0.002891% (1/34590) of Latino alleles in gnomAD v2. In v3, present in 0.04651% (1/2150) of alleles in the “other” subpopulation. These were the only alleles.

BS2

identified in at least 1 unaffected parent of a proband with features of a RASopathy; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000209112.10).

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