NM_006270.5(RRAS):c.43C>T (p.Arg15Trp) AND Noonan syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 21, 2020
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:: RCV002471738.1

Allele description [Variation Report for NM_006270.5(RRAS):c.43C>T (p.Arg15Trp)]

NM_006270.5(RRAS):c.43C>T (p.Arg15Trp)

Gene:

RRAS:RAS related [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_006270.5(RRAS):c.43C>T (p.Arg15Trp)

HGVS:

NC_000019.10:g.49640056G>A
NG_042222.1:g.5088C>T
NG_141834.1:g.167G>A
NM_006270.5:c.43C>TMANE SELECT
NP_006261.1:p.Arg15Trp
NC_000019.9:g.50143313G>A
NM_006270.4:c.43C>T

Protein change:

R15W

Molecular consequence:

NM_006270.5:c.43C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002766636	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 21, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24705357, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002766636

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 21, 2020)

germline

clinical testing

PubMed (2)
[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

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

Flex E, Jaiswal M, Pantaleoni F, Martinelli S, Strullu M, Fansa EK, Caye A, De Luca A, Lepri F, Dvorsky R, Pannone L, Paolacci S, Zhang SC, Fodale V, Bocchinfuso G, Rossi C, Burkitt-Wright EM, Farrotti A, Stellacci E, Cecchetti S, Ferese R, Bottero L, et al.

Hum Mol Genet. 2014 Aug 15;23(16):4315-27. doi: 10.1093/hmg/ddu148. Epub 2014 Apr 4.

PubMed [citation]

PMID:: 24705357
PMCID:: PMC4103678

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766636.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS-3C. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease (ClinVar, PMID: 24705357). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan (exon 1). (N) 0302 - Variant is present in a region of low coverage in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	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: Dec 24, 2022

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