ClinVar Miner

Submissions for variant NM_153676.4(USH1C):c.2167C>T (p.Gln723Ter) (rs146451547)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211746 SCV000064957 uncertain significance not specified 2018-12-13 criteria provided, single submitter clinical testing The p.Gln723X variant in USH1C has been previously identified in the homozygous state in one African American individual with hearing loss with no reported eye findings (LMM unpublished data). This variant has been reported in ClinVar (Vari ant ID: 47990). However, it has also been identified in 0.25% (59/24002) African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst This variant leads to a premature stop codon at position 723. Howeve r, the p.Gln723X variant is located in exon 20 of an alternatively spiced isofor m. This splice isoform has been reported to be expressed in the inner ear and n ot in the retina based upon studies in mice (Ouyang 2002). However, there is ins ufficient evidence in humans to support whether variants in the exons unique to this isoform would result in hearing loss or Usher syndrome. In addition to the p.Gln723X variant, there is a second putative loss of function variant that is a lso unique to this transcript that is present at a high frequency in the general population and as such, it is not clear whether variants in this exon are disea se causing (DiStefano 2018). In summary, due to the uncertainty whether variants affecting the exons specific to the transcript in which p.Gln723X lies, the cli nical significance of the p.Gln723X variant is uncertain. ACMG/AMP criteria appl ied: PVS1_Moderate, BS1_Supporting.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725879 SCV000340206 likely pathogenic not provided 2016-04-08 criteria provided, single submitter clinical testing
Invitae RCV000725879 SCV001065968 benign not provided 2018-11-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004552 SCV001163631 pathogenic Usher syndrome type 1 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000041266 SCV000238426 likely pathogenic Deafness, autosomal recessive 18 2015-02-20 no assertion criteria provided research This heterozygous variant (c.2167C>T; p.Gln723X) variant has not been previously reported in the literature but has been reported in the ClinVar database as likely pathogenic by the Laboratory for Molecular Medicine in two families. This variant is predicted to result in a premature protein truncation in only one isoform (NM_153676.3). Missense mutations have been reported in exons specific to this isoform in patients with non-syndromic hearing loss, suggesting that alterations affecting only this isoform may result in a clinical phenotype (PMID: 12136232). This isoform is known to be expressed in the inner ear but not in the eye, which may explain the lack of an eye phenotype in the reported patients. Because the mode of inheritance for this condition does not match the observed inheritance of the disorder in the family this variant was not considered to be causative of the patient’s clinical presentation of hearing loss.
Counsyl RCV000984230 SCV001132306 uncertain significance Usher syndrome, type 1C 2019-04-07 no assertion criteria provided clinical testing
Counsyl RCV000041266 SCV001132307 uncertain significance Deafness, autosomal recessive 18 2019-04-07 no assertion criteria provided clinical testing

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