ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.680T>C (p.Leu227Pro)

gnomAD frequency: 0.00001  dbSNP: rs764317969
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS RCV001527418 SCV001738417 likely pathogenic Niemann-Pick disease, type B 2021-04-25 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553551 SCV001774441 pathogenic Sphingomyelin/cholesterol lipidosis 2024-10-07 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.680T>C (p.Leu227Pro) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247098 control chromosomes. c.680T>C has been reported in the literature in individuals affected with Niemann-Pick Disease (Pittis_2004, Bonetto_2005, Zanetti_2020, Deshpande_2021). These data indicate that the variant may be associated with disease. At least two functional papers report this variant results in deficient activity of acid sphingomyelinase (Dardis_2005, Rodrguez-Pascau_2009). The following publications have been ascertained in the context of this evaluation (PMID: 26499107, 16010684, 15241805, 19405096, 27725636, 16264060, 27435900, 32036093, 34273913). ClinVar contains an entry for this variant (Variation ID: 553073). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000668447 SCV004205060 pathogenic Niemann-Pick disease, type A 2023-10-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003767963 SCV004569719 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-01-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 553073). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 227 of the SMPD1 protein (p.Leu227Pro). This variant is present in population databases (rs764317969, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 15241805, 34273913). This variant is also known as c.674T>C (p.L225P). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 16010684, 19405096). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV003767963 SCV005684500 likely pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2024-01-22 criteria provided, single submitter clinical testing
Counsyl RCV000668447 SCV000793052 uncertain significance Niemann-Pick disease, type A 2017-08-01 flagged submission clinical testing

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