Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002547586 | SCV003266780 | uncertain significance | Primary ciliary dyskinesia | 2022-04-29 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1583 of the DNAH5 protein (p.Ala1583Thr). This variant is present in population databases (rs374072143, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1048956). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH5 protein function. 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, |
RCV001354408 | SCV001549021 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The DNAH5 p.Ala1583Thr variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs374072143) and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 2 of 282694 chromosomes at a frequency of 0.000007075 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7208 chromosomes (freq: 0.000139) and African in 1 of 24964 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or South Asian populations. The p.Ala1583 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 (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. |