ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.5821G>C (p.Ala1941Pro) (rs368058473)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723912 SCV000202639 uncertain significance not provided 2014-04-27 criteria provided, single submitter clinical testing
Invitae RCV000167972 SCV000218620 uncertain significance Jeune thoracic dystrophy 2018-08-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 1941 of the DYNC2H1 protein (p.Ala1941Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs368058473, ExAC 0.03%). This variant has not been reported in the literature in individuals with DYNC2H1-related disease. ClinVar contains an entry for this variant (Variation ID: 167012). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000723912 SCV000517476 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing The A1941P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A1941P variant is observed in 6/30078 (0.0199%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). The A1941P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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