NM_007373.4(SHOC2):c.187G>A (p.Gly63Arg) AND RASopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 24, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003655332.1

Allele description [Variation Report for NM_007373.4(SHOC2):c.187G>A (p.Gly63Arg)]

NM_007373.4(SHOC2):c.187G>A (p.Gly63Arg)

Gene:

SHOC2:SHOC2 leucine rich repeat scaffold protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q25.2

Genomic location:

Preferred name:

NM_007373.4(SHOC2):c.187G>A (p.Gly63Arg)

HGVS:

NC_000010.11:g.110964545G>A
NG_028922.1:g.50003G>A
NM_001269039.3:c.187G>A
NM_001324336.2:c.187G>A
NM_001324337.2:c.187G>A
NM_007373.4:c.187G>AMANE SELECT
NP_001255968.1:p.Gly63Arg
NP_001311265.1:p.Gly63Arg
NP_001311266.1:p.Gly63Arg
NP_031399.2:p.Gly63Arg
LRG_753t1:c.187G>A
LRG_753:g.50003G>A
NC_000010.10:g.112724303G>A
NM_007373.3:c.187G>A

Protein change:

G63R

Links:

Molecular consequence:

NM_001269039.3:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001324336.2:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001324337.2:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007373.4:c.187G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004537068	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29907801, 30417923, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004537068

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 24, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA.

Genet Med. 2019 Feb;21(2):417-425. doi: 10.1038/s41436-018-0062-0. Epub 2018 Jun 15. Erratum in: Genet Med. 2018 Jul 26;:.

PubMed [citation]

PMID:: 29907801

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

Bessis D, Miquel J, Bourrat E, Chiaverini C, Morice-Picard F, Abadie C, Manna F, Baumann C, Best M, Blanchet P, Bursztejn AC, Capri Y, Coubes C, Giuliano F, Guillaumont S, Hadj-Rabia S, Jacquemont ML, Jeandel C, Lacombe D, Mallet S, Mazereeuw-Hautier J, Molinari N, et al.

Br J Dermatol. 2019 Jun;180(6):1438-1448. doi: 10.1111/bjd.17404. Epub 2019 Jan 18.

PubMed [citation]

PMID:: 30417923

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004537068.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHOC2 protein function. ClinVar contains an entry for this variant (Variation ID: 981608). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 29907801, 30417923; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 63 of the SHOC2 protein (p.Gly63Arg).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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