NM_005343.4(HRAS):c.179G>A (p.Gly60Asp) AND Costello syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 4, 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:: RCV001387769.7

Allele description [Variation Report for NM_005343.4(HRAS):c.179G>A (p.Gly60Asp)]

NM_005343.4(HRAS):c.179G>A (p.Gly60Asp)

Genes:

HRAS:HRas proto-oncogene, GTPase [Gene - OMIM - HGNC]
LRRC56:leucine rich repeat containing 56 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_005343.4(HRAS):c.179G>A (p.Gly60Asp)

Other names:

p.G60D:GGC>GAC

HGVS:

NC_000011.10:g.533877C>T
NG_007666.1:g.6674G>A
NM_001130442.3:c.179G>A
NM_001318054.2:c.-141G>A
NM_005343.4:c.179G>AMANE SELECT
NM_176795.5:c.179G>A
NP_001123914.1:p.Gly60Asp
NP_005334.1:p.Gly60Asp
NP_789765.1:p.Gly60Asp
LRG_506t1:c.179G>A
LRG_506:g.6674G>A
LRG_506p1:p.Gly60Asp
NC_000011.9:g.533877C>T
NM_005343.2:c.179G>A

Protein change:

G60D

Links:

dbSNP: rs730880460

NCBI 1000 Genomes Browser:

rs730880460

Molecular consequence:

NM_001318054.2:c.-141G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.179G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005343.4:c.179G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_176795.5:c.179G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Costello syndrome (CSTLO)
Synonyms:: Faciocutaneoskeletal syndrome; FCS syndrome
Identifiers:: MONDO: MONDO:0009026; MedGen: C0587248; Orphanet: 3071; OMIM: 218040

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001588484	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 4, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28027064, 25914166, 26467218, 28139825, 30732632, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001588484

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 4, 2022)

germline

clinical testing

PubMed (6)
[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

Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome.

Pelc M, Ciara E, Jezela-Stanek A, Kugaudo M, Cieślikowska A, Jurkiewicz D, Janeczko M, Chrzanowska K, Krajewska-Walasek M, Skórka A.

Clin Dysmorphol. 2017 Apr;26(2):83-90. doi: 10.1097/MCD.0000000000000165.

PubMed [citation]

PMID:: 28027064

An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.

Gripp KW, Sol-Church K, Smpokou P, Graham GE, Stevenson DA, Hanson H, Viskochil DH, Baker LC, Russo B, Gardner N, Stabley DL, Kolbe V, Rosenberger G.

Am J Med Genet A. 2015 Sep;167A(9):2085-97. doi: 10.1002/ajmg.a.37128. Epub 2015 Apr 25.

PubMed [citation]

PMID:: 25914166
PMCID:: PMC4830354

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001588484.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant is not present in population databases (gnomAD no frequency). This variant disrupts the p.Gly60 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been observed in individuals with HRAS-related conditions (PMID: 28027064), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects HRAS function (PMID: 28139825). 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 expected to disrupt HRAS protein function. ClinVar contains an entry for this variant (Variation ID: 40436). This missense change has been observed in individual(s) with clinical features of Costello and Noonan syndrome (PMID: 25914166, 26467218, 28139825, 30732632). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 60 of the HRAS protein (p.Gly60Asp). For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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