NM_002039.4(GAB1):c.347G>A (p.Gly116Glu) AND Autosomal recessive nonsyndromic hearing loss 26

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 15, 2018
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:: RCV000656478.2

Allele description [Variation Report for NM_002039.4(GAB1):c.347G>A (p.Gly116Glu)]

NM_002039.4(GAB1):c.347G>A (p.Gly116Glu)

Gene:

GAB1:GRB2 associated binding protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q31.21

Genomic location:

Preferred name:

NM_002039.4(GAB1):c.347G>A (p.Gly116Glu)

HGVS:

NC_000004.12:g.143415751G>A
NM_002039.4:c.347G>AMANE SELECT
NM_207123.3:c.347G>A
NP_002030.2:p.Gly116Glu
NP_997006.1:p.Gly116Glu
NC_000004.11:g.144336904G>A
NM_207123.2:c.347G>A

Protein change:

G116E; GLY116GLU

Links:

OMIM: 604439.0001; dbSNP: rs1553950635

NCBI 1000 Genomes Browser:

rs1553950635

Molecular consequence:

NM_002039.4:c.347G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_207123.3:c.347G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 26
Synonyms:: Deafness, autosomal recessive 26
Identifiers:: MONDO: MONDO:0011553; MedGen: C1854275; Orphanet: 90636; OMIM: 605428

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000778447	OMIM	no assertion criteria provided	Pathogenic (Aug 6, 2021)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11101839, 29408807
SCV000883155	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 15, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 29408807, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000778447

OMIM

no assertion criteria provided

Pathogenic
(Aug 6, 2021)

germline

literature only

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

SCV000883155

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 15, 2018)

germline

curation

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	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Dominant modifier DFNM1 suppresses recessive deafness DFNB26.

Riazuddin S, Castelein CM, Ahmed ZM, Lalwani AK, Mastroianni MA, Naz S, Smith TN, Liburd NA, Friedman TB, Griffith AJ, Riazuddin S, Wilcox ER.

Nat Genet. 2000 Dec;26(4):431-4.

PubMed [citation]

PMID:: 11101839

Modifier variant of METTL13 suppresses human GAB1-associated profound deafness.

Yousaf R, Ahmed ZM, Giese AP, Morell RJ, Lagziel A, Dabdoub A, Wilcox ER, Riazuddin S, Friedman TB, Riazuddin S.

J Clin Invest. 2018 Apr 2;128(4):1509-1522. doi: 10.1172/JCI97350. Epub 2018 Mar 12.

PubMed [citation]

PMID:: 29408807
PMCID:: PMC5873844

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000778447.2

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

Description

In 8 deaf and 7 hearing members of a large consanguineous Pakistani family (PK2) with prelingual severe-to-profound nonsyndromic hearing loss (DFNM26; 605428), originally studied by Riazuddin et al. (2000), Yousaf et al. (2018) identified homozygosity for a c.347G-A transition (c.347G-A, NM_207123) in exon 2 of the GAB1 gene, resulting in a gly116-to-glu (G116E) substitution at a highly conserved residue within the PH domain. The G116E variant was not found in 380 Pakistani and 192 Indian control chromosomes, or in the 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. Functional analysis of the lipid-binding function of the mutant GAB1 PH domain showed significantly lower amounts bound to phosphoinositides compared to the wildtype PH domain. In addition, phenotypes of gab1-null morphant zebrafish were partially rescued by coinjection of G116E mutant mRNA compared to wildtype GAB1, suggesting that G116E represents a hypomorphic allele. Nonpenetrant hearing members of the family were also heterozygous for a missense mutation in the METTL13 gene (617987.0001), which was not present in any of the deaf members of the family.

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

From SIB Swiss Institute of Bioinformatics, SCV000883155.1

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

Description

This variant is interpreted as Pathogenic, for Deafness, autosomal recessive, 26. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1-Moderate => PP1 upgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29408807). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://prosite.expasy.org/PDOC50003) (https://www.uniprot.org/uniprot/Q13480) (https://www.ncbi.nlm.nih.gov/pubmed/29408807). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29408807).

#	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: Apr 23, 2022

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