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 [Variation Report for NM_012414.4(RAB3GAP2):c.1276C>T (p.Arg426Cys)]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992710	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 12, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23420520, 25741868
SCV002265556	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23420520, 24891604, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000992710

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 12, 2018)

germline

clinical testing

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

SCV002265556

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 26, 2024)

germline

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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

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

From Invitae, SCV002265556.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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: Jun 23, 2024

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