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]

Variant: NM_005633.3(SOS1):c.3286T>A (p.Ser1096Thr)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA1624230

477722 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4a76e95a-d97a-4b9a-9e4d-2a0cb69afd78

Approved on: 2020-03-19

Published on: 2020-03-23

HGVS expressions

NM_005633.3:c.3286T>A

NM_005633.3(SOS1):c.3286T>A (p.Ser1096Thr)

NC_000002.12:g.38995183A>T

CM000664.2:g.38995183A>T

NC_000002.11:g.39222324A>T

CM000664.1:g.39222324A>T

NC_000002.10:g.39075828A>T

NG_007530.1:g.130281T>A

ENST00000395038.6:c.3286T>A

ENST00000402219.6:c.3286T>A

ENST00000426016.5:c.3286T>A

Uncertain Significance

BS2 BS1 BP4 PP2 BA1 PM2 PM1

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.3286T>A (p.Ser1096Thr) variant in SOS1 has been observed in 0.01864% (24/128738) of non-Finnish European chromosomes in gnomAD v2.1.1. This variant was seen in several individuals whose clinical presentations lacked clear associations with a RASopathy (PMIDs: 22589294, 26580448, 27153395; Invitae internal data, SCV000659145.1; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=14) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data). 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.

BS2

Seen by GeneDx in 14 unaffected parents from 14 different trios, but not well-phenotyped. Also observed in several individuals whose clinical presentations lacked clear associations with a RASopathy (PMIDs: 22589294, 26580448, 27153395; Invitae internal data, SCV000659145.1; Baylor internal data; Greenwood Genetic Center internal data).

BS1

Present in 0.01864% (24/128738) of non-Finnish European chromosomes in gnomAD v2; present in 0.03252% (21/64584) of non-Finnish European chromosomes in gnomAD v3 (95% CI is 0.02178%).

BP4

REVEL score 0.333. Splicing is not predicted to be impacted in Alamut. No animals in UCSC have threonine at this position.

PP2

SOS1 is a missense-constrained gene, but evidence is leaning benign.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

Does not occur in aa 420-500.

Curation History

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