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

Total submissions: 7

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