NM_005343.4(HRAS):c.178G>A (p.Gly60Ser) AND Costello syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 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:: RCV000818197.7

Allele description [Variation Report for NM_005343.4(HRAS):c.178G>A (p.Gly60Ser)]

NM_005343.4(HRAS):c.178G>A (p.Gly60Ser)

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.178G>A (p.Gly60Ser)

HGVS:

NC_000011.10:g.533878C>T
NG_007666.1:g.6673G>A
NM_001130442.3:c.178G>A
NM_001318054.2:c.-142G>A
NM_005343.4:c.178G>AMANE SELECT
NM_176795.5:c.178G>A
NP_001123914.1:p.Gly60Ser
NP_005334.1:p.Gly60Ser
NP_789765.1:p.Gly60Ser
LRG_506t1:c.178G>A
LRG_506:g.6673G>A
LRG_506p1:p.Gly60Ser
NC_000011.9:g.533878C>T
NM_005343.2:c.178G>A

Protein change:

G60S

Links:

dbSNP: rs1589792804

NCBI 1000 Genomes Browser:

rs1589792804

Molecular consequence:

NM_001318054.2:c.-142G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001130442.3:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005343.4:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_176795.5:c.178G>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
SCV000958797	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25914166, 28139825, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000958797

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 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

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

Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics.

Gripp KW, Kolbe V, Brandenstein LI, Rosenberger G.

Clin Genet. 2017 Sep;92(3):332-337. doi: 10.1111/cge.12980. Epub 2017 Mar 30.

PubMed [citation]

PMID:: 28139825

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958797.4

#	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. This variant disrupts the p.Gly60 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25914166, 28139825). 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 expected to disrupt HRAS protein function. ClinVar contains an entry for this variant (Variation ID: 660897). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 60 of the HRAS protein (p.Gly60Ser).

#	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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