ClinVar Miner

Submissions for variant NM_001369.2(DNAH5):c.6791G>A (p.Ser2264Asn) (rs78484669)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000322718 SCV000453091 uncertain significance Ciliary dyskinesia, primary, 3 2016-07-25 criteria provided, single submitter clinical testing The DNAH5 c.6791G>A (p.Ser2264Asn) variant is a missense variant that was first reported by Hornef et al. (2006) and subsequently noted by Failly et al. (2009) and Raidt et al. (2014) in two siblings with primary ciliary dyskinesia. Both individuals were compound heterozygous for the p.Ser2264Asn variant and a frameshift variant. The p.Ser2264Asn variant was absent from 140 control chromosomes (Hornef et al. 2006) but is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project. This frequency is based on only one allele in a region of good sequencing coverage and the variant is therefore presumed to be rare. High-speed video microscopy of respiratory epithelial cells from one of the siblings showed completely immotile cilia, suggesting the variant, at least in combination with the additional frameshift variant, impaired ciliary function (Hornef et al. 2006). Based on the evidence, the p.Ser2264Asn variant is classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000807221 SCV000947264 likely pathogenic Primary ciliary dyskinesia 2019-07-18 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 2264 of the DNAH5 protein (p.Ser2264Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs78484669, ExAC 0.001%). This variant has been observed to segregate with primary ciliary dyskinesia in a family (PMID: 16627867). ClinVar contains an entry for this variant (Variation ID: 351068). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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