ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.670A>C (p.Lys224Gln)

gnomAD frequency: 0.00015  dbSNP: rs111033194
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037870 SCV000061532 uncertain significance not specified 2018-04-04 criteria provided, single submitter clinical testing The p.Lys224Gln variant in GJB2 has been previously reported in 8 individuals wi th hearing loss (Antoniadi 2000, Pandya 2003, Samanich 2007, Kokotas 2010, Shan 2010, LMM data); however a variant affecting the remaining DFNB1 allele (GJB2 a nd GJB6 genes) was not identified in any of the individuals. This variant has be en identified in 27/124038 European chromosomes and in 5/34358 Latino chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033194), though, this frequency is not high enough to rule out a path ogenic role. Computational prediction tools and conservation analyses do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Lys224Gln variant is uncertain. ACMG/AMP Criteria ap plied: None.
Athena Diagnostics RCV000710115 SCV000613523 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing
Counsyl RCV000666342 SCV000790618 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-03-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763879 SCV000894814 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 2021-10-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037870 SCV000917434 uncertain significance not specified 2023-08-24 criteria provided, single submitter clinical testing Variant summary: GJB2 c.670A>C (p.Lys224Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250298 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00014 vs 0.025), allowing no conclusion about variant significance. c.670A>C has been reported in the literature in multiple individuals affected with non-syndromic hearing loss, including both heterozygous individuals without a second variant identified and homozygous individuals (Tekin_2007, Ozylmaz_2019) without evidence of cosegregation with disease provided. These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Non-Syndromic Hearing Loss. One publication reports experimental evidence evaluating an impact on protein function (Spagnol_2016), however it does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 17366579, 22567369, 12865758, 17666888, 19230829, 20381175, 23695287, 19081147, 17357124, 22016077, 10874298, 26542351, 31620696, 30245029). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Additionally, a published expert curation also classified the variant as uncertain significance (Deafness Variation Database, Azaiez_2018). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037870 SCV001156572 uncertain significance not specified 2018-12-24 criteria provided, single submitter clinical testing The GJB2 c.670A>C; p.Lys224Gln variant (rs111033194) is reported in the literature in individuals with hearing loss and in several normal-hearing controls (Antoniadi 2000, Matos 2011, Pandya 2003, Putcha 2007, Samanich 2007). This variant does not exhibit dominant inheritance (Antoniadi 2000), and, to our knowledge, it has not been reported in trans to another pathogenic variant in affected individuals (Antoniadi 2000, Pandya 2003, Putcha 2007, Samanich 2007). This variant is reported in ClinVar (Variation ID: 44765), and it is found in the general population with an overall allele frequency of 0.01% (36/279154 alleles) in the Genome Aggregation Database. The lysine at codon 224 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the lack of clinical and functional data, the significance of the p.Lys224Gln variant is uncertain at this time. References: Antoniadi T et al. Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness. Hum Mutat. 2000;16(1):7-12. Matos TD et al. Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association. Genet Res Int. 2011;2011:827469. Pandya A et al. Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. Genet Med. 2003 Jul-Aug;5(4):295-303. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Samanich J et al. Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. Am J Med Genet A. 2007 Apr 15;143A(8):830-8.
GeneDx RCV000710115 SCV001875061 uncertain significance not provided 2024-10-01 criteria provided, single submitter clinical testing Observed in the heterozygous state without a second variant in multiple individuals with hearing loss in the published literature (PMID: 10874298, 12865758, 17357124, 20381175); Observed in the apparent homozygous state in two patients with hearing loss in the published literature (PMID: 17444514, 31620696) and not observed in the homozygous state in controls; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19230829, 17357124, 12172392, 25262649, 25388846, 26990548, 30245029, 19081147, 26542351, 20059378, 17666888, 17366579, 16125251, 22567369, 21844220, 20381175, 12865758, 31620696, 33199029, 10874298, 17444514, 36048236, 38253033)
Labcorp Genetics (formerly Invitae), Labcorp RCV000710115 SCV003292077 uncertain significance not provided 2022-10-12 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 224 of the GJB2 protein (p.Lys224Gln). This variant is present in population databases (rs111033194, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 17444514). ClinVar contains an entry for this variant (Variation ID: 44765). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Natera, Inc. RCV000666342 SCV001463357 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing

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