rs773846324
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
This summary comes from the ClinGen Evidence Repository: The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID:17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6904209/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.677T>G | p.Val226Gly | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.677T>G | p.Val226Gly | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.677T>G | p.Val226Gly | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.677T>G | p.Val226Gly | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247688Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134678
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1460126Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19AN XY: 726460
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 30, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 28, 2017 | The p.Val226Gly variant in GJB2 has been reported in the heterozygous state in o ne individual with hearing loss (Putcha 2007). This variant has been identified in 1/11448 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs773846324). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Val226Gly variant is uncertain. - |
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2017 | - - |
Nonsyndromic genetic hearing loss Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Sep 26, 2023 | The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (less than or equal to 0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID: 17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2021 | This sequence change replaces valine with glycine at codon 226 of the GJB2 protein (p.Val226Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs773846324, ExAC 0.009%). This variant has been observed in individual(s) with deafness (PMID: 20201936; Invitae). ClinVar contains an entry for this variant (Variation ID: 447450). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at