ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1498T>C (p.Tyr500His)

gnomAD frequency: 0.00003  dbSNP: rs771336819
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674077 SCV000799351 uncertain significance Niemann-Pick disease, type A 2018-05-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001861832 SCV002264709 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-05-20 criteria provided, single submitter clinical testing This variant disrupts the p.Tyr500 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 26851525), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 557879). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 23356216, 33675270). This variant is present in population databases (rs771336819, gnomAD 0.03%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 500 of the SMPD1 protein (p.Tyr500His).
Baylor Genetics RCV000674077 SCV004203240 likely pathogenic Niemann-Pick disease, type A 2024-02-19 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004742566 SCV005359317 pathogenic SMPD1-related disorder 2024-03-08 no assertion criteria provided clinical testing The SMPD1 c.1498T>C variant is predicted to result in the amino acid substitution p.Tyr500His. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease (Table 1, Zhang et al. 2013. PubMed ID: 23356216; Table 3, Hu et al. 2021. PubMed ID: 33675270). At least one patient, who was homozygous for the variant, had reduced ASM activity levels (Hu et al. 2021. PubMed ID: 33675270). Of note, a different variant that affects the same amino acid residue (c.1498T>A, p.Tyr500Asn) has also been reported to be causative for Niemann-Pick disease (described as c.1495T>A in Ding et al. 2016. PubMed ID: 26851525). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD. We interpret this variant as pathogenic.

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