ClinVar Miner

Submissions for variant NM_001277115.2(DNAH11):c.8870C>G (p.Ala2957Gly) (rs369875222)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536038 SCV000624180 uncertain significance Primary ciliary dyskinesia 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 2957 of the DNAH11 protein (p.Ala2957Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs369875222, ExAC 0.07%) but has not been reported in the literature in individuals with a DNAH11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The glycine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000658448 SCV000780220 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing The A2957G variant in the DNAH11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A2957G variant is observed in 7/22694 (0.01%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016). The A2957G 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. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret A2957G as a variant of uncertain significance.

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