rs727504302
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_004004.6(GJB2):c.239A>G(p.Gln80Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q80K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: GJB2 c.239A>G (p.Gln80Arg) results in a conservative amino acid change located in the connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes (gnomAD). c.239A>G has been reported in the literature in the homozygous state in an individual affected with Non-Syndromic Hearing Loss and as an uninformative genotype (heterozygosity versus compound heterozygosity not specified) in at least one other affected individual (e.g. Uyguner_2003, Chen_2011, Xing_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the same amino acid (i.e. pQ80H, p.Q80L, pQ80K, p.Q80P) have been reported in association with hearing loss in the literature (HGMD database), suggesting the Gln80 residue may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21777984, 12791041, 27785406). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.