ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.1630C>T (p.His544Tyr) (rs745815071)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825321 SCV000966616 uncertain significance not specified 2018-02-27 criteria provided, single submitter clinical testing The p.His544Tyr variant in COL4A4 has not been previously reported in individual s with hearing loss or Alport syndrome but was present in 0.04% (12/30780) of So uth Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.; dbSNP rs745815071). Although this variant has been seen in t he general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that the missense variant may not impact the protein, while splice prediction tools sugg est a possible creation of a cryptic 5' splice site due to the nucleotide change ; however, it should be noted these computational tools are not predictive enoug h to determine. In summary, the clinical significance of the p.His544Tyr variant is uncertain. ACMG/AMP Criteria applied: PP3.
Illumina Clinical Services Laboratory,Illumina RCV001138069 SCV001298094 uncertain significance Alport syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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