ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.298del (p.His100fs) (rs775828835)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586317 SCV000698242 likely pathogenic Deafness, autosomal recessive 1A 2016-06-07 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.298delC (p.His100Metfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.K112fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121268 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Deafness variation database lists variant with classification of pathogenic. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.
GeneDx RCV001009145 SCV001168960 likely pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The c.298delC likely pathogenic variant in the GJB2 gene causes a frameshift starting with codon Histidine 100, changes this amino acid to a Methionine residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.His100MetfsX12. This likely pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 127 correct amino acids are replaced with 11 incorrect amino acids. The c.298delC variant has been observed in 4/33582 (0.0119%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). Although this variant has not been previously reported to our knowledge, we classify this variant as likely pathogenic.

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