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.1230G>A (p.Gln410=)

CA136077

40665 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: dcfb56fe-0b80-4c22-b9fc-d5d834b1bf38

Approved on: 2024-09-17

Published on: 2024-10-02

HGVS expressions

NM_005633.3:c.1230G>A

NM_005633.3(SOS1):c.1230G>A (p.Gln410=)

NC_000002.12:g.39023198C>T

CM000664.2:g.39023198C>T

NC_000002.11:g.39250339C>T

CM000664.1:g.39250339C>T

NC_000002.10:g.39103843C>T

NG_007530.1:g.102266G>A

ENST00000472480.2:n.1110G>A

ENST00000685279.1:c.-4G>A

ENST00000688043.1:n.1451G>A

ENST00000689668.1:n.1237G>A

ENST00000690679.1:c.1417G>A

ENST00000690876.1:c.1119G>A

ENST00000691229.1:c.1119G>A

ENST00000692089.1:c.1119G>A

ENST00000692620.1:c.-4G>A

ENST00000402219.8:c.1230G>A

ENST00000395038.6:c.1230G>A

ENST00000402219.6:c.1230G>A

ENST00000426016.5:c.1230G>A

ENST00000472480.1:n.74G>A

NM_001382394.1:c.1209G>A

NM_001382395.1:c.1230G>A

NM_005633.4:c.1230G>A

Benign

BP4 BP5 BP7 BA1

BS1 PP3 PM2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1230G>A variant in the SOS1 gene is a synonymous (silent) variant (p.Gln410=) at a nucleotide that is not highly conserved and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1. This variant has been identified in patients with an alternate molecular basis for disease (BP5; Partners LMM internal data GTR Lab ID: 21766, ClinVar SCV000062189.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 09/17/2024)

BP4

Computational prediction tool SpliceAI conservation analysis suggest that the p.Gln410= variant does not impact the protein (BP4).

BP5

The c.1230G>A (p.Gln410=) variant in SOS1 has been identified in 2 patients with known pathogenic variants in PTPN11 (BP5; Partners LMM internal data GTR Lab ID: 21766 ClinVar SCV000062189.6).

BP7

This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7).

BA1

The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1.

BS1

The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1.

PP3

Computational prediction tools and conservation analysis suggest that the p.Gln410= variant does not impact the protein (BP4).

PM2

The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1.

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