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NM_012414.4(RAB3GAP2):c.1276C>T (p.Arg426Cys) AND multiple conditions

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 26, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000850507.12

Allele description

NM_012414.4(RAB3GAP2):c.1276C>T (p.Arg426Cys)

Gene:
RAB3GAP2:RAB3 GTPase activating non-catalytic protein subunit 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q41
Genomic location:
Preferred name:
NM_012414.4(RAB3GAP2):c.1276C>T (p.Arg426Cys)
HGVS:
  • NC_000001.11:g.220191279G>A
  • NG_015837.2:g.86223C>T
  • NM_012414.4:c.1276C>TMANE SELECT
  • NP_036546.2:p.Arg426Cys
  • NC_000001.10:g.220364621G>A
  • NG_015837.1:g.86223C>T
  • NM_012414.3:c.1276C>T
Protein change:
R426C; ARG426CYS
Links:
OMIM: 609275.0003; dbSNP: rs587777167
NCBI 1000 Genomes Browser:
rs587777167
Molecular consequence:
  • NM_012414.4:c.1276C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Martsolf syndrome (MARTS)
Synonyms:
Cataract mental retardation hypogonadism; Congenital cataract with intellectual disability and hypogonadotropic hypogonadism syndrome
Identifiers:
MONDO: MONDO:0023910; MedGen: C0796037; Orphanet: 1387; OMIM: PS212720
Name:
Warburg micro syndrome 2 (WARBM2)
Synonyms:
MICRO SYNDROME 2
Identifiers:
MONDO: MONDO:0013641; MedGen: C3280214; Orphanet: 2510; OMIM: 614225

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000992710Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 12, 2018) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002265556Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 26, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome.

Handley MT, Morris-Rosendahl DJ, Brown S, Macdonald F, Hardy C, Bem D, Carpanini SM, Borck G, Martorell L, Izzi C, Faravelli F, Accorsi P, Pinelli L, Basel-Vanagaite L, Peretz G, Abdel-Salam GM, Zaki MS, Jansen A, Mowat D, Glass I, Stewart H, Mancini G, et al.

Hum Mutat. 2013 May;34(5):686-96. doi: 10.1002/humu.22296.

PubMed [citation]
PMID:
23420520
See all PubMed Citations (4)

Details of each submission

From Baylor Genetics, SCV000992710.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002265556.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 426 of the RAB3GAP2 protein (p.Arg426Cys). This variant is present in population databases (rs587777167, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of Martsolf syndrome (PMID: 23420520; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 100787). 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 RAB3GAP2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAB3GAP2 function (PMID: 24891604). 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: Sep 16, 2024