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).
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, single submitter
- Submissions:
- 2
- First in ClinVar:
- Jun 12, 2018
- Most recent Submission:
- Aug 14, 2021
- Last evaluated:
- Oct 15, 2018
- Accession:
- VCV000545492.2
- Variation ID:
- 545492
- Description:
- single nucleotide variant
Help
NM_002039.4(GAB1):c.347G>A (p.Gly116Glu)
- Allele ID
- 535752
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 4q31.21
- Genomic location
- 4: 143415751 (GRCh38) GRCh38 UCSC
- 4: 144336904 (GRCh37) GRCh37 UCSC
- HGVS
-
Nucleotide Protein Molecular
consequenceNM_002039.4:c.347G>A MANE Select NP_002030.2:p.Gly116Glu missense NM_207123.3:c.347G>A NP_997006.1:p.Gly116Glu missense NC_000004.12:g.143415751G>A NC_000004.11:g.144336904G>A - Protein change
- G116E
- Other names
- -
- Canonical SPDI
- NC_000004.12:143415750:G:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- OMIM: 604439.0001
- dbSNP: rs1553950635
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 2 | criteria provided, single submitter | Oct 15, 2018 | RCV000656478.2 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Oct 15, 2018)
|
criteria provided, single submitter
Method: curation
|
Autosomal recessive nonsyndromic hearing loss 26
Affected status: unknown
Allele origin:
germline
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000883155.1
First in ClinVar: Jun 12, 2018 Last updated: Jun 12, 2018 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Aug 06, 2021)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 26 (1 family)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000778447.2
First in ClinVar: Jun 12, 2018 Last updated: Aug 14, 2021 |
Comment on evidence:
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 … (more)
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. (less)
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. | Yousaf R | The Journal of clinical investigation | 2018 | PMID: 29408807 |
| Dominant modifier DFNM1 suppresses recessive deafness DFNB26. | Riazuddin S | Nature genetics | 2000 | PMID: 11101839 |
Text-mined citations for rs1553950635...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 25, 2022