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NM_004985.5(KRAS):c.35G>T (p.Gly12Val) AND RASopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 13, 2023
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:
RCV003539760.1

Allele description

NM_004985.5(KRAS):c.35G>T (p.Gly12Val)

Gene:
KRAS:KRAS proto-oncogene, GTPase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p12.1
Genomic location:
Preferred name:
NM_004985.5(KRAS):c.35G>T (p.Gly12Val)
Other names:
p.G12V:GGT>GTT; NP_004976.2:p.Gly12Val
HGVS:
  • NC_000012.12:g.25245350C>A
  • NG_007524.2:g.10654G>T
  • NM_001369786.1:c.35G>T
  • NM_001369787.1:c.35G>T
  • NM_004985.5:c.35G>TMANE SELECT
  • NM_033360.4:c.35G>T
  • NP_001356715.1:p.Gly12Val
  • NP_001356716.1:p.Gly12Val
  • NP_004976.2:p.Gly12Val
  • NP_203524.1:p.Gly12Val
  • LRG_344t1:c.35G>T
  • LRG_344t2:c.35G>T
  • LRG_344:g.10654G>T
  • LRG_344p1:p.Gly12Val
  • LRG_344p2:p.Gly12Val
  • NC_000012.11:g.25398284C>A
  • NG_007524.1:g.10571G>T
  • NM_004985.3:c.35G>T
  • NM_004985.4:c.35G>T
  • NM_033360.2:c.35G>T
  • P01116:p.Gly12Val
Protein change:
G12V; GLY12VAL
Links:
UniProtKB: P01116#VAR_006840; OMIM: 190070.0006; OMIM: 190070.0026; dbSNP: rs121913529
NCBI 1000 Genomes Browser:
rs121913529
Molecular consequence:
  • NM_001369786.1:c.35G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369787.1:c.35G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004985.5:c.35G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033360.4:c.35G>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004295856Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 13, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.

Gremer L, Merbitz-Zahradnik T, Dvorsky R, Cirstea IC, Kratz CP, Zenker M, Wittinghofer A, Ahmadian MR.

Hum Mutat. 2011 Jan;32(1):33-43. doi: 10.1002/humu.21377. Epub 2010 Dec 9.

PubMed [citation]
PMID:
20949621
PMCID:
PMC3117284

TLN-4601 suppresses growth and induces apoptosis of pancreatic carcinoma cells through inhibition of Ras-ERK MAPK signaling.

Campbell PM, Boufaied N, Fiordalisi JJ, Cox AD, Falardeau P, Der CJ, Gourdeau H.

J Mol Signal. 2010 Nov 2;5:18. doi: 10.1186/1750-2187-5-18.

PubMed [citation]
PMID:
21044336
PMCID:
PMC2990749
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV004295856.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the KRAS protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 12583). 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 KRAS protein function. Experimental studies have shown that this missense change affects KRAS function (PMID: 20949621, 21044336). This variant disrupts the p.Gly12 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Aug 11, 2024