ClinVar Miner

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

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Total submissions: 5
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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; Keratoderma palmoplantar deafness; 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.

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