ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1562T>G (p.Leu521Arg)

dbSNP: rs1057517826
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414036 SCV000490820 likely pathogenic not provided 2015-08-11 criteria provided, single submitter clinical testing The L521R variant has not been published as a pathogenic variant, nor has it been reported as a benignpolymorphism to our knowledge. The L521R variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position where amino acids with similar properties to Leucine aretolerated across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Furthermore, missense variants in nearby residues (H516Q, E517V, Y519C, N522S,Q525H) have been reported in the Human Gene Mutation Database in association with Niemann-Pick disease(Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, thisvariant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variantcannot be excluded.
Breakthrough Genomics, Breakthrough Genomics RCV004596176 SCV005088893 likely pathogenic Niemann-Pick disease, type A 2021-03-30 criteria provided, single submitter clinical testing This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant has not been previously reported in individuals with SMPD1-related disorders. However, several other missense variants in the vicinity of identified variant have been previously reported as ‘likely pathogenic’ in the context of Niemann-Pick disease, type A and type B in ClinVar database.

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