ClinVar Genomic variation as it relates to human health

NM_000543.4(SMPD1):c.911T>C(L304P, aka L302P) is classified as pathogenic in the context of SMPD1-related Niemann-Pick disease. Sources cited for classification include the following: PMID 18815062, 21502868 and 1391960. Classification of NM_000543.4(SMPD1):c.911T>C(L304P, aka L302P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: The c.911T>C (p.Leu304Pro, alternatively known as L302P) variant in SMPD1 gene is a missense change that alters a highly conserved nucleotide. The variant, located in the MPP_ASMase domain, is predicted to be deleterious by 5/5 in silico tools. In vitro/vivo functional studies showed that this variant caused severely reduced enzymatic activity. The variant was absent from the large and broad cohorts of the ExAC project (0/121366 chromosomes). The variant was identified in several affected individuals, including multiple homozygotes, with an established diagnosis of NPD-A. Levran (1992) reported the frequency of the variant of interest in affected individuals of Ashkenazi Jewish origin with type A NPD was greater than 20% and called it the second most common disease-causing allele in AJ. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.

The p.Leu304Pro variant in SMPD1 (also known as p.Leu302Pro due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 8401540, 1391960, 18815062) and has been identified in 0.040% (4/10080) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074124). 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: 2989) as Pathogenic by Counsyl, Integrated Genetics, EGL Genetic Diagnostics, OMIM, and GeneReviews. In vitro functional studies provide some evidence that the p.Leu304Pro variant may impact protein function (PMID: 1391960, 18815062). 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 at least 1 affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Leu304Pro variant is pathogenic (VariaitionID: 2990; PMID: 8401540, 1391960, 18815062). The p.Leu304Pro variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in functional domain and supports pathogenicity (PMID: 27725636, 30788890). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease. In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the in vitro functional studies, its importance in maintaining structure, and its presence in affected homozygous and compound heterozygous individuals. ACMG/AMP Criteria applied: PS3, PM3, PM1, PM2_supporting, PP3, PP4 (Richards 2015).

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 304 of the SMPD1 protein (p.Leu304Pro). This variant is present in population databases (rs120074124, gnomAD 0.04%). This missense change has been observed in individuals with Niemann-Pick type A disease (PMID: 1391960, 8401540, 10464620, 26169695). This variant is also known as p.L302P,. ClinVar contains an entry for this variant (Variation ID: 2989). 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: 1391960, 26499107). For these reasons, this variant has been classified as Pathogenic.

Common pathogenic variant in Ashkenazi Jewish patients with Niemann-Pick disease, type A (PMID: 1391960); Expression studies show that L304P abolishes sphingomyelin phosphodiesterase 1 enzyme activity (PMID: 1391960); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18815062, 8401540, 23535491, 37347058, 26320887, 36907956, 37069638, 24446175, 30788890, 26169695, 32280632, 1391960)

1 of 3 common variants that accounts for more than 90% of pathogenic variants in persons of Ashkenazi Jewish ancestry with Niemann-Pick disease type-A