ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.663G>C (p.Lys221Asn) (rs375599392)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037869 SCV000061531 uncertain significance not specified 2012-04-17 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Lys221Asn varia nt in GJB2 has not been reported in the literature in any individuals with heari ng loss nor previously identified by our laboratory. However, this variant has b een identified in 0.01% (1/6984) of European American chromosomes in a broad pop ulation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/ ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of this variant cannot be determined with certainty.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000505528 SCV000599766 uncertain significance Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Counsyl RCV000505528 SCV000795432 uncertain significance Deafness, autosomal recessive 1A 2017-11-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765114 SCV000896336 uncertain significance Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037869 SCV001737872 uncertain significance not specified 2021-06-01 criteria provided, single submitter clinical testing Variant summary: GJB2 c.663G>C (p.Lys221Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 248358 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (4e-05 vs 0.00034), allowing no conclusion about variant significance. c.663G>C has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Stanghellini_2014, Kashef_2015). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001778681 SCV002015519 uncertain significance not provided 2021-11-01 criteria provided, single submitter clinical testing Reported in the heterozygous state without a second variant in an individual with profound hearing loss in the published literature (Stanghellini et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 25555641, 25401782)
Natera, Inc. RCV000505528 SCV001463358 uncertain significance Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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