ClinVar Miner

Submissions for variant NM_024009.3(GJB3):c.586G>A (p.Ala196Thr)

gnomAD frequency: 0.00002  dbSNP: rs138304650
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Goettingen RCV000855419 SCV000994921 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2019-10-02 criteria provided, single submitter clinical testing The c.586G>A GJB3-variant (p.Ala196Thr) is found at a relatively low frequency (gnomAD & ExAC population frequency: 0.0025%) within the general population and has a pathogenic computational verdict due to 10 pathogenic predictions from DANN, DEOGEN2, FATHMM, FATHMM-MKL, FATHMM-XF, LRT, M-CAP, MutationAssessor, MutationTaster and SIFT vs. 3 benign predictions from PROVEAN, PrimateAI and SIFT4G. In our facility the variant was found in compound heterozygous state with a pathogenic GJB2-Variant (c.101T>C / p.Met34Thr) in an affected patient with non-syndromic congenital bilateral deafness. Segregation analysis revealed the same variant combination in the unaffected, healthy father. Thus, we consider this variant a variant of unknown significance (VUS), with possibly benign character. The possibility of this variant being pathogenic in homozygous state can not be excluded.
Ambry Genetics RCV004029276 SCV004876993 uncertain significance Inborn genetic diseases 2023-12-18 criteria provided, single submitter clinical testing The c.586G>A (p.A196T) alteration is located in exon 2 (coding exon 1) of the GJB3 gene. This alteration results from a G to A substitution at nucleotide position 586, causing the alanine (A) at amino acid position 196 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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