ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.6551T>C (p.Val2184Ala) (rs200805455)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534344 SCV000624280 uncertain significance Primary ciliary dyskinesia 2017-02-22 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2184 of the DNAH5 protein (p.Val2184Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs200805455, ExAC 0.02%) but has not been reported in the literature in individuals with a DNAH5-related disease. 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, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358439 SCV001554171 likely benign not provided no assertion criteria provided clinical testing The DNAH5 p.Val2184Ala variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200805455) and ClinVar (classified as a VUS by Invitae). The variant was identified in control databases in 19 of 282754 chromosomes at a frequency of 0.000067 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was also observed in the European (non-Finnish) population in 19 of 129082 chromosomes (freq: 0.000147), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Val2184 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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