NM_004985.5(KRAS):c.101C>T (p.Pro34Leu) AND Noonan syndrome 3

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 23, 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:: RCV003152670.1

Allele description [Variation Report for NM_004985.5(KRAS):c.101C>T (p.Pro34Leu)]

NM_004985.5(KRAS):c.101C>T (p.Pro34Leu)

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.101C>T (p.Pro34Leu)

Other names:

p.P34L:CCA>CTA; NM_004985.4(KRAS):c.101C>T

HGVS:

NC_000012.12:g.25245284G>A
NG_007524.2:g.10720C>T
NM_001369786.1:c.101C>T
NM_001369787.1:c.101C>T
NM_004985.5:c.101C>TMANE SELECT
NM_033360.4:c.101C>T
NP_001356715.1:p.Pro34Leu
NP_001356716.1:p.Pro34Leu
NP_004976.2:p.Pro34Leu
NP_203524.1:p.Pro34Leu
LRG_344t1:c.101C>T
LRG_344t2:c.101C>T
LRG_344:g.10720C>T
LRG_344p1:p.Pro34Leu
LRG_344p2:p.Pro34Leu
NC_000012.11:g.25398218G>A
NG_007524.1:g.10637C>T
NM_004985.3:c.101C>T
NM_004985.4:c.101C>T
P01116:p.Pro34Leu

Protein change:

P34L

Links:

UniProtKB: P01116#VAR_064852; dbSNP: rs104894366

NCBI 1000 Genomes Browser:

rs104894366

Molecular consequence:

NM_001369786.1:c.101C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369787.1:c.101C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004985.5:c.101C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033360.4:c.101C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome 3 (NS3)
Synonyms:: KRAS gene related Noonan syndrome
Identifiers:: MONDO: MONDO:0012371; MedGen: C1860991; Orphanet: 648; OMIM: 609942

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003841315	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20949621, 17056636, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003841315

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical 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

Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.

Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K.

J Med Genet. 2007 Feb;44(2):131-5. Epub 2006 Oct 20.

PubMed [citation]

PMID:: 17056636
PMCID:: PMC2598066

See all PubMed Citations (3)

Details of each submission

From 3billion, SCV003841315.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040454). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17056636, 20949621). A different missense change at the same codon (p.Pro34Arg) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012590). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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