NM_006912.6(RIT1):c.338A>T (p.Glu113Val) AND Noonan syndrome 8

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 4, 2022
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:: RCV003076185.2

Allele description [Variation Report for NM_006912.6(RIT1):c.338A>T (p.Glu113Val)]

NM_006912.6(RIT1):c.338A>T (p.Glu113Val)

Gene:

RIT1:Ras like without CAAX 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_006912.6(RIT1):c.338A>T (p.Glu113Val)

HGVS:

NC_000001.11:g.155904402T>A
NG_033885.1:g.12001A>T
NM_001256820.2:c.230A>T
NM_001256821.2:c.389A>T
NM_006912.6:c.338A>TMANE SELECT
NP_001243749.1:p.Glu77Val
NP_001243750.1:p.Glu130Val
NP_008843.1:p.Glu113Val
LRG_1372t1:c.338A>T
LRG_1372:g.12001A>T
LRG_1372p1:p.Glu113Val
NC_000001.10:g.155874193T>A

Protein change:

E113V

Molecular consequence:

NM_001256820.2:c.230A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256821.2:c.389A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006912.6:c.338A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome 8 (NS8)
Identifiers:: MONDO: MONDO:0014143; MedGen: C3809233; Orphanet: 648; OMIM: 615355

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003473543	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31573083, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003473543

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 4, 2022)

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

Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café-au-lait macules.

Castellanos E, Rosas I, Negro A, Gel B, Alibés A, Baena N, Pineda M, Pi G, Pintos G, Salvador H, Lázaro C, Blanco I, Vilageliu L, Brems H, Grinberg D, Legius E, Serra E.

Clin Genet. 2020 Feb;97(2):264-275. doi: 10.1111/cge.13649. Epub 2019 Dec 12.

PubMed [citation]

PMID:: 31573083

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003473543.2

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

Description

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. 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 not expected to disrupt RIT1 protein function. This missense change has been observed in individual(s) with clinical features of RIT1-related conditions (PMID: 31573083). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 113 of the RIT1 protein (p.Glu113Val).

#	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 14, 2024

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