ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1801G>A (p.Ala601Thr)

gnomAD frequency: 0.00001  dbSNP: rs750433951
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671468 SCV000796444 uncertain significance Niemann-Pick disease, type A 2017-12-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001215758 SCV001387520 likely pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-08-04 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 601 of the SMPD1 protein (p.Ala601Thr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 555615). This missense change has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 27884455; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs750433951, gnomAD 0.0009%).

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