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NM_005343.4(HRAS):c.546G>A (p.Met182Ile) AND Costello syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 25, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000229010.14

Allele description [Variation Report for NM_005343.4(HRAS):c.546G>A (p.Met182Ile)]

NM_005343.4(HRAS):c.546G>A (p.Met182Ile)

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.546G>A (p.Met182Ile)
HGVS:
  • NC_000011.10:g.532660C>T
  • NG_007666.1:g.7891G>A
  • NM_001130442.3:c.546G>A
  • NM_001318054.2:c.309G>A
  • NM_005343.4:c.546G>AMANE SELECT
  • NM_176795.5:c.*115G>A
  • NP_001123914.1:p.Met182Ile
  • NP_001304983.1:p.Met103Ile
  • NP_005334.1:p.Met182Ile
  • LRG_506t1:c.546G>A
  • LRG_506:g.7891G>A
  • LRG_506p1:p.Met182Ile
  • NC_000011.9:g.532660C>T
  • NM_005343.2:c.546G>A
Protein change:
M103I
Links:
dbSNP: rs748639813
NCBI 1000 Genomes Browser:
rs748639813
Molecular consequence:
  • NM_176795.5:c.*115G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001130442.3:c.546G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318054.2:c.309G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005343.4:c.546G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000288863Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 25, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003811237Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jun 7, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000288863.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 182 of the HRAS protein (p.Met182Ile). This variant is present in population databases (rs748639813, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 240138). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. 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.

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

From Revvity Omics, Revvity, SCV003811237.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024