ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.647_650del (p.Arg216fs) (rs587783647)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146027 SCV000193181 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153313 SCV000227312 pathogenic not provided 2015-03-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217521 SCV000271228 likely pathogenic Rare genetic deafness 2015-06-08 criteria provided, single submitter clinical testing The p.Arg216fs variant in GJB2 has been previously reported in one individual wi th hearing loss who was compound heterozygous for a second pathogenic variant in GJB2 (Prasad 2000, variant reported as c.645_648delTAGA). This variant was abse nt from large population studies, though the ability of these studies to accurat ely detect indels may be limited. This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 216 and leads to a new termination codon 17 amino acids downstream, thus resulting in a longer protein (the abnormal protein is 5 amino acids longer than the normal pro tein). This variant is expected to disrupt the normal function of the protein; h owever additional data is needed to confirm this. In summary, although additiona l studies are required to fully establish its clinical significance, the p.Arg21 6fs variant is likely pathogenic based on its presence in compound heterozygosit y with a known pathogenic variant in an affected individual and the predicted im pact to the protein.
Counsyl RCV000175766 SCV000487633 likely pathogenic Deafness, autosomal recessive 1A 2016-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000411907 SCV000487634 likely pathogenic Deafness, autosomal dominant 3a 2016-06-21 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000175766 SCV000599765 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000153313 SCV000613522 pathogenic not provided 2015-07-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000175766 SCV000698270 pathogenic Deafness, autosomal recessive 1A 2016-09-07 criteria provided, single submitter clinical testing Variant summary: The c.647_650delGATA (p.Arg216Ilefs) variant in GJB2 gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present in the large control population dataset of ExAC at a low frequency 0.000026 (3/117776 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.025) in this gene. The variant of interest has been reported in multiple affected individuals in compound heterozygous state with confirmed dx of NSHL. In addition, multiple reputable databases/clinical laboratories classified this variant as Pathogenic. Taken together, the variant was classified as Pathogenic.
GeneDx RCV000153313 SCV000709969 likely pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing The c.647_650delGATA variant has been reported previously in association with hearing loss (Azaiez et al., 2004; Tang et al., 2006; Hernández-Juárez et al., 2014). The deletion causes a frameshift starting with codon Arginine 216, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Arg216IlefsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is observed in 12/33554 (0.036%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be likely pathogenic.

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