NM_005343.4(HRAS):c.189G>C (p.Glu63Asp) AND Costello syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 20, 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:: RCV002705677.3

Allele description [Variation Report for NM_005343.4(HRAS):c.189G>C (p.Glu63Asp)]

NM_005343.4(HRAS):c.189G>C (p.Glu63Asp)

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.189G>C (p.Glu63Asp)

HGVS:

NC_000011.10:g.533867C>G
NG_007666.1:g.6684G>C
NG_121454.1:g.176C>G
NM_001130442.3:c.189G>C
NM_001318054.2:c.-131G>C
NM_005343.4:c.189G>CMANE SELECT
NM_176795.5:c.189G>C
NP_001123914.1:p.Glu63Asp
NP_005334.1:p.Glu63Asp
NP_789765.1:p.Glu63Asp
LRG_506t1:c.189G>C
LRG_506:g.6684G>C
LRG_506p1:p.Glu63Asp
NC_000011.9:g.533867C>G

Protein change:

E63D

Molecular consequence:

NM_001318054.2:c.-131G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.189G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005343.4:c.189G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_176795.5:c.189G>C - 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
SCV002998643	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 20, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17412879, 25070542, 26001911, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002998643

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 20, 2022)

germline

clinical testing

PubMed (4)
[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

Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation.

van der Burgt I, Kupsky W, Stassou S, Nadroo A, Barroso C, Diem A, Kratz CP, Dvorsky R, Ahmadian MR, Zenker M.

J Med Genet. 2007 Jul;44(7):459-62. Epub 2007 Apr 5.

PubMed [citation]

PMID:: 17412879
PMCID:: PMC2598013

Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation.

Bolocan A, Quijano-Roy S, Seferian AM, Baumann C, Allamand V, Richard P, Estournet B, Carlier R, Cavé H, Gartioux C, Blin N, Le Moing AG, Gidaro T, Germain DP, Fardeau M, Voit T, Servais L, Romero NB.

Neuromuscul Disord. 2014 Nov;24(11):993-8. doi: 10.1016/j.nmd.2014.06.437. Epub 2014 Jun 28.

PubMed [citation]

PMID:: 25070542

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002998643.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Glu63 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17412879, 25070542, 26001911). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 HRAS protein function. This variant has not been reported in the literature in individuals affected with HRAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 63 of the HRAS protein (p.Glu63Asp).

#	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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