ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.4072G>A (p.Gly1358Ser) (rs752638332)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700755 SCV000829526 uncertain significance Primary ciliary dyskinesia 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1358 of the DNAH5 protein (p.Gly1358Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs752638332, ExAC 0.01%). This variant has not been reported in the literature in individuals with 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356211 SCV001551318 uncertain significance not provided no assertion criteria provided clinical testing  The DNAH5 p.G1358S variant was not identified in the literature, however it was identified in dbSNP (ID: rs752638332) and in ClinVar (classified as uncertain significance by Invitae for the associated condition Ciliary dyskinesia). The variant was identified in control databases in 9 of 280742 chromosomes at a frequency of 0.00003206 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 2 of 7128 chromosomes (freq: 0.000281), South Asian in 2 of 30540 chromosomes (freq: 0.000065) and European (non-Finnish) in 5 of 128174 chromosomes (freq: 0.000039), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.G1358 residue is conserved in across mammals and other organisms however computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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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