ClinVar Miner

Submissions for variant NM_000543.4(SMPD1):c.748A>C (p.Ser250Arg) (rs750779804)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409846 SCV000487192 likely pathogenic Niemann-Pick disease, type A 2016-10-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780730 SCV000918240 pathogenic not specified 2018-02-09 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.748A>C (p.Ser250Arg) results in a non-conservative amino acid change located in ApaH type Calcineurin-like phosphoesterase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244428 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (1.7e-05 vs 0.0022), allowing no conclusion about variant significance. c.748A>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type A and B (Hollak_2012, Zhang_2013, Toth_2011, Diggelen_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hollak_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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