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

gnomAD frequency: 0.00003  dbSNP: rs375599392

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000505528	SCV000795432	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2017-11-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765114	SCV000896336	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	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	2024-04-02	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 estimated 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. The following publications have been ascertained in the context of this evaluation (PMID: 25388846, 25401782, 25555641). ClinVar contains an entry for this variant (Variation ID: 44764). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001778681	SCV002015519	uncertain significance	not provided	2024-04-18	criteria provided, single submitter	clinical testing	Reported in the heterozygous state without a second variant in patients with sensorineural hearing loss in the published literature (PMID: 34515852, 25401782); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 25555641, 25401782, 34515852)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001778681	SCV002218918	uncertain significance	not provided	2022-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 221 of the GJB2 protein (p.Lys221Asn). This variant is present in population databases (rs375599392, gnomAD 0.008%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 25401782, 25555641). ClinVar contains an entry for this variant (Variation ID: 44764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics	RCV001778681	SCV005621979	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools predict that this variant is not damaging.
Natera, Inc.	RCV000505528	SCV001463358	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing