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.1655G>C (p.Arg552Thr)

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CA261728

40682 (ClinVar)

Gene: SOS1

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 29f14367-9d8d-4cd9-a97b-74d1d13b0a74

Approved on: 2019-04-23

Published on: 2024-08-23

HGVS expressions

NM_005633.3:c.1655G>C

NM_005633.3(SOS1):c.1655G>C (p.Arg552Thr)

NC_000002.12:g.39022773C>G

CM000664.2:g.39022773C>G

NC_000002.11:g.39249914C>G

CM000664.1:g.39249914C>G

NC_000002.10:g.39103418C>G

NG_007530.1:g.102691G>C

ENST00000472480.2:n.1535G>C

ENST00000685279.1:c.422G>C

ENST00000688043.1:n.1876G>C

ENST00000689668.1:n.1662G>C

ENST00000690876.1:c.1544G>C

ENST00000691229.1:c.1544G>C

ENST00000692089.1:c.1544G>C

ENST00000692620.1:c.422G>C

ENST00000402219.8:c.1655G>C

ENST00000395038.6:c.1655G>C

ENST00000402219.6:c.1655G>C

ENST00000426016.5:c.1655G>C

NM_001382394.1:c.1634G>C

NM_001382395.1:c.1655G>C

NM_005633.4:c.1655G>C

Pathogenic

PS4_Moderate PP3 PP2 PM6 PM2 PM1_Strong

PS2 PS1 PS3 BP3 BP2 BP4 BP1 BP5 BP7 BA1 PP4 PP1 PVS1 PM5 PM4 PM3 BS2 BS4 BS3 BS1

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID: 21387466, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The p.Arg552 residue has been defined as a hotspot by the RAS EP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). 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 missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg552Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PM2, PM6, PP2, PP3.

PS4_Moderate

Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 1 patient with an unknown family history. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere. PubMed:21387466

Patient 2 of the 5 patients reported in this study was sequenced and determined to have the p.Arg552Thr variant. the patient had typical NS, cryporchidism, decreased platelet aggregation, moderate ventriculomegaly, intellectual disability PubMed:19352411

PP3

Variant has REVEL score of 0.955

PP2

SOS1 is a PP2 gene

PM6

GeneDx: Identified this variant in a de novo case of NS. Internal data.

PM2

This variant is absent from gnomAD.

PM1_Strong

This variant is at the hotspot that has been defined as p.Arg552. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement.

PS2