ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.880C>A (p.Gln294Lys)

gnomAD frequency: 0.00001  dbSNP: rs120074128
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169297 SCV000220616 pathogenic Niemann-Pick disease, type A 2014-08-20 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781865 SCV000920241 pathogenic not specified 2017-11-22 criteria provided, single submitter clinical testing Variant summary: The SMPD1 c.880C>A (p.Gln294Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/246300 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361). This variant has been reported in numerous acid sphingomyelinase deficiency patients with neurologic abnormalities, both as a homozygous and compound heterozygous allele (McGovern_2004, Pittis_2004, Wasserstein_2006, and Pavlu-Pereira_2005). Transient expression of the variant in ASM-deficient human skin fibroblasts in the homozygous state showed ASM activity <5% of WT (Pavlu-Pereira_2005). Taken together, this variant is classified as pathogenic.
Invitae RCV000812595 SCV000952913 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 294 of the SMPD1 protein (p.Gln294Lys). This variant is present in population databases (rs120074128, gnomAD 0.003%). This missense change has been observed in individuals with Niemann-Pick disease i (PMID: 9266408, 15241805, 15877209, 17011332). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln292Lys. ClinVar contains an entry for this variant (Variation ID: 2994). 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). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248931 SCV001422707 pathogenic Sphingomyelin/cholesterol lipidosis 2020-01-22 criteria provided, single submitter curation The p.Gln294Lys variant in SMPD1 (also known as p.Gln292Lys due to a difference in cDNA numbering) has been reported in at least 24 individuals with Niemann-Pick disease, segregated with disease in 6 affected relatives from 3 families (PMID: 15241805, 17011332, 15877209, 14681755), and has been identified in 0.002% (2/113716) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs120074128). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 2994) as Pathogenic by Counsyl, Integrated Genetics, and OMIM. In vitro functional studies provide some evidence that the p.Gln294Lys variant may impact protein function (PMID: 15877209). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 6 affected homozygotes and in combination with reported pathogenic variants in at least 13 individuals with Niemann-Pick disease increases the likelihood that the p.Gln294Lys variant is pathogenic (VariationID: 167710, 2990, 2982, 371341, 2991, 189096, 371576; PMID: 15877209, 17011332, 14681755). The phenotype of numerous individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 15877209, 14681755). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in affected homozygotes and compound heterozygotes, in vitro functional studies, cosegregation with disease, and the phenotype of individuals with the variant being highly specific for disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2, PP1_moderate, PP3, PP4 (Richards 2015).
Ambry Genetics RCV002512693 SCV003563159 pathogenic Inborn genetic diseases 2021-08-20 criteria provided, single submitter clinical testing The c.880C>A (p.Q294K) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a C to A substitution at nucleotide position 880, causing the glutamine (Q) at amino acid position 294 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251426) total alleles studied. The highest observed frequency was <0.01% (2/113716) of European (non-Finnish) alleles. This alteration has been reported in the homozygous and compound heterozygous state with a second SMPD1 alteration in multiple individuals with SMPD1-related Niemann-Pick disease (Harzer, 2003; Pavl, 1997; Pavl-Pereira, 2005; Pittis, 2004; Reunert, 2016; Wang, 2017; Wasserstein, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV003333947 SCV004042509 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing SMPD1: PM3:Very Strong, PM2, PM5, PP4:Moderate, PS3:Supporting
Baylor Genetics RCV000169297 SCV004203208 pathogenic Niemann-Pick disease, type A 2024-02-27 criteria provided, single submitter clinical testing
OMIM RCV000003128 SCV000023286 pathogenic Niemann-Pick disease, type B 2005-01-01 no assertion criteria provided literature only
OMIM RCV000003129 SCV000023287 pathogenic Niemann-pick disease, intermediate, protracted neurovisceral 2005-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000169297 SCV002092251 pathogenic Niemann-Pick disease, type A 2017-03-17 no assertion criteria provided clinical testing

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