ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.424C>T (p.Leu142Phe) (rs373769397)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181273 SCV000233562 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing The L142F variant of uncertain significance in the DSP gene has not been published as pathogenic or been reported as benign to our knowledge. However, L142F has been identified, both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for cardiac genetic testing at GeneDx. This variant is observed in 4/24,020 (0.017%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). L142F is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000810828 SCV000951064 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 142 of the DSP protein (p.Leu142Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs373769397, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 199849). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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