NM_005633.3(SOS1):c.1655G>T (p.Arg552Met) AND Noonan syndrome and Noonan-related syndrome

Clinical significance:Likely pathogenic (Last evaluated: May 10, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000787996.1

Allele description [Variation Report for NM_005633.3(SOS1):c.1655G>T (p.Arg552Met)]

NM_005633.3(SOS1):c.1655G>T (p.Arg552Met)

Gene:
SOS1:SOS Ras/Rac guanine nucleotide exchange factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p22.1
Genomic location:
Preferred name:
NM_005633.3(SOS1):c.1655G>T (p.Arg552Met)
Other names:
NM_005633.3(SOS1):c.1655G>T
HGVS:
  • NC_000002.12:g.39022773C>A
  • NG_007530.1:g.102691G>T
  • NM_005633.3:c.1655G>T
  • NP_005624.2:p.Arg552Met
  • LRG_754t1:c.1655G>T
  • LRG_754:g.102691G>T
  • LRG_754p1:p.Arg552Met
  • NC_000002.11:g.39249914C>A
Protein change:
R552M
Links:
dbSNP: rs397517154
NCBI 1000 Genomes Browser:
rs397517154
Molecular consequence:
  • NM_005633.3:c.1655G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Noonan syndrome and Noonan-related syndrome
Identifiers:
MONDO: MONDO:0020297; MedGen: CN260604; Orphanet: 98733

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000927025ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
Likely pathogenic
(May 10, 2019)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Citations

PubMed

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, Dimitriadoy S, Liu DL, Kantheti HS, Saghafinia S, Chakravarty D, Daian F, Gao Q, Bailey MH, Liang WW, Foltz SM, Shmulevich I, Ding L, Heins Z, Ochoa A, Gross B, Gao J, et al.

Cell. 2018 Apr 5;173(2):321-337.e10. doi: 10.1016/j.cell.2018.03.035.

PubMed [citation]
PMID:
29625050
PMCID:
PMC6070353

SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations.

Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, et al.

Hum Mutat. 2011 Jul;32(7):760-72. doi: 10.1002/humu.21492. Epub 2011 Apr 28.

PubMed [citation]
PMID:
21387466
PMCID:
PMC3118925

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927025.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The c.1655G>T (p.Arg552Met) variant has been identified in at least 3 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx internal data; GTR Lab IDs 26957; SCV000565586.5 PMID: 21387466). his AA residue has been specified as a hotspot for variation. 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Met variant may impact the protein (PP3). 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PP2, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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