NM_004985.5(KRAS):c.441G>T (p.Lys147Asn) AND RASopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 9, 2024
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:: RCV003540291.1

Allele description

NM_004985.5(KRAS):c.441G>T (p.Lys147Asn)

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.441G>T (p.Lys147Asn)

HGVS:

NC_000012.12:g.25225623C>A
NG_007524.2:g.30381G>T
NM_001369786.1:c.441G>T
NM_001369787.1:c.441G>T
NM_004985.5:c.441G>TMANE SELECT
NM_033360.4:c.441G>T
NP_001356715.1:p.Lys147Asn
NP_001356716.1:p.Lys147Asn
NP_004976.2:p.Lys147Asn
NP_203524.1:p.Lys147Asn
LRG_344t1:c.441G>T
LRG_344t2:c.441G>T
LRG_344:g.30381G>T
LRG_344p1:p.Lys147Asn
LRG_344p2:p.Lys147Asn
NC_000012.11:g.25378557C>A

Protein change:

K147N

Molecular consequence:

NM_001369786.1:c.441G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369787.1:c.441G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004985.5:c.441G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033360.4:c.441G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004316660	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21797849, 23059812, 29158550, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004316660

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 9, 2024)

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

Two novel germline KRAS mutations: expanding the molecular and clinical phenotype.

Stark Z, Gillessen-Kaesbach G, Ryan MM, Cirstea IC, Gremer L, Ahmadian MR, Savarirayan R, Zenker M.

Clin Genet. 2012 Jun;81(6):590-4. doi: 10.1111/j.1399-0004.2011.01754.x. Epub 2011 Aug 18.

PubMed [citation]

PMID:: 21797849

Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes.

Cirstea IC, Gremer L, Dvorsky R, Zhang SC, Piekorz RP, Zenker M, Ahmadian MR.

Hum Mol Genet. 2013 Jan 15;22(2):262-70. doi: 10.1093/hmg/dds426. Epub 2012 Oct 11.

PubMed [citation]

PMID:: 23059812

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004316660.1

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

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 147 of the KRAS protein (p.Lys147Asn). 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. 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 with a positive predictive value of 95%. This variant disrupts the p.Lys147 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21797849, 23059812, 29158550). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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: Feb 20, 2024

ClinVar

Relating variation to medicine