ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.1121T>C (p.Ile374Thr) (rs147499872)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228082 SCV000287054 uncertain significance Primary ciliary dyskinesia 2019-07-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 374 of the DNAH5 protein (p.Ile374Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs147499872, ExAC 0.1%). This variant has been observed in combination with another DNAH5 variant in an individual affected with primary ciliary dyskinesia (PMID: 23261302). ClinVar contains an entry for this variant (Variation ID: 39651). 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: "Benign"; 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.
Illumina Clinical Services Laboratory,Illumina RCV000032855 SCV000453278 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.
GeneDx RCV000523858 SCV000617399 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing The I374T variant in the DNAH5 gene has been reported previously in trans with another DNAH5 variant in an individual with primary ciliary dyskinesia (Knowles et al., 2013). The I374T variant is observed in 63/65,796 (0.096%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The I374T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I374T as a variant of uncertain significance.
Counsyl RCV000032855 SCV000800597 uncertain significance Ciliary dyskinesia, primary, 3 2017-09-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000032855 SCV000897207 uncertain significance Ciliary dyskinesia, primary, 3 2018-10-31 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000228082 SCV001431739 uncertain significance Primary ciliary dyskinesia 2019-04-18 criteria provided, single submitter clinical testing
OMIM RCV000032855 SCV000056624 pathogenic Ciliary dyskinesia, primary, 3 2013-01-10 no assertion criteria provided literature only

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