ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.670A>C (p.Lys224Gln) (rs111033194)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Inc RCV000710115 SCV000613523 uncertain significance not provided 2018-03-23 criteria provided, single submitter clinical testing
Counsyl RCV000666342 SCV000790618 uncertain significance Deafness, autosomal recessive 1A 2017-03-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763879 SCV000894814 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
Integrated Genetics/Laboratory Corporation of America RCV000037870 SCV000917434 uncertain significance not specified 2017-10-31 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.670A>C (p.Lys224Gln) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 38/275882 control chromosomes (including gnomAD) at a frequency of 0.0001377, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). Multiple publications have cited the variant in affected individuals including a homozyous patient (Tekin_2007), however, multiple reported individuals were indicated to only carry the variant of interest and a second variant not being identified. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant with conflicting classifications "uncertain significance" or "benign." Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
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.

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