Submissions for variant NM_000543.5(SMPD1):c.1133G>A (p.Arg378His)

gnomAD frequency: 0.00006  dbSNP: rs559088058

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670710	SCV000795601	uncertain significance	Niemann-Pick disease, type A	2017-11-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000670710	SCV001163676	pathogenic	Niemann-Pick disease, type A	2024-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056291	SCV001220727	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the SMPD1 protein (p.Arg378His). This variant is present in population databases (rs559088058, gnomAD 0.02%). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 15877209, 17011332, 19405096, 23252888). This variant is also known as R376H. ClinVar contains an entry for this variant (Variation ID: 554977). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 15877209). This variant disrupts the p.Arg378 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 17011332), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509398	SCV001716083	pathogenic	not provided	2021-01-12	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP3, PP4
GeneDx	RCV001509398	SCV001794694	uncertain significance	not provided	2024-02-08	criteria provided, single submitter	clinical testing	Identified in multiple individuals with Parkinson disease; however, this variant was also observed in many unaffected controls (PMID: 26377108); Published functional studies may suggest a damaging effect resulting in an enzyme with approximately 40% activity compared to wild-type enzyme (PMID: 15877209); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also denoted as R376H due to alternative nomenclature; This variant is associated with the following publications: (PMID: 27725636, 35861376, 12369017, 34426522, 26499107, 17011332, 33100332, 34867278, 30788890, 32071839, 15234149, Chew2023[preprint], 19405096, 15877209, 26377108, 23252888, 26169295)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000670710	SCV002583732	likely pathogenic	Niemann-Pick disease, type A	2022-09-28	criteria provided, single submitter	clinical testing	PS3, PM1, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226361	SCV003922729	pathogenic	Sphingomyelin/cholesterol lipidosis	2023-03-18	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1133G>A (p.Arg378His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH (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 7.2e-05 in 249216 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (7.2e-05 vs 0.0022), allowing no conclusion about variant significance. c.1133G>A has been reported in the literature in individuals affected with Niemann-Pick Disease (example, PMID: 12369017, 15877209, 19405096, 23252888, 26169295). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 40% of normal activity in a heterozygous background (example, PMID: 15877209). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000670710	SCV005051974	pathogenic	Niemann-Pick disease, type A	2024-02-01	criteria provided, single submitter	curation