ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.1715T>G (p.Leu572Trp) (rs137878131)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000765816 SCV000453266 uncertain significance Ciliary dyskinesia, primary, 3 2018-01-13 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.
Invitae RCV000336304 SCV000546346 uncertain significance Primary ciliary dyskinesia 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with tryptophan at codon 572 of the DNAH5 protein (p.Leu572Trp). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and tryptophan. This variant is present in population databases (rs137878131, ExAC 0.2%). This variant has been observed as heterozygous in an individual with Kartagener's syndrome (PMID: 29402277). However, in that individual, a second variant was not reported in DNAH5, and a homozygous pathogenic variant was identified in ZMYND10. ClinVar contains an entry for this variant (Variation ID: 351208). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000765816 SCV000897206 uncertain significance Ciliary dyskinesia, primary, 3 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825330 SCV000966625 uncertain significance not specified 2018-03-22 criteria provided, single submitter clinical testing The p.Leu572Trp variant in DNAH5 has not been previously reported in individuals with primary ciliary dyskinesia, but has been identified in 0.1% (147/120780) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs13787813). Computational prediction tools and conse rvation analysis suggest that the p.Leu572Trp variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Leu572Trp variant is uncertain. ACMG/A MP Criteria applied: PP3.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000336304 SCV001431756 uncertain significance Primary ciliary dyskinesia 2018-10-12 criteria provided, single submitter clinical testing

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