Submissions for variant NM_000543.5(SMPD1):c.1268A>G (p.His423Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003037365	SCV003439784	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 423 of the SMPD1 protein (p.His423Arg). This variant is present in population databases (rs767492080, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick A disease (PMID: 16434659, 19405096). This variant is also known as H421R. ClinVar contains an entry for this variant (Variation ID: 2136989). 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%. This variant disrupts the p.His423 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12369017, 17876723, 27338287, 28600779). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331417	SCV004039185	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1268A>G (p.His423Arg, it was also known as p.His421Arg in the literature) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249054 control chromosomes (gnomAD). c.1268A>G has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease (McGovern_2006, Rodrguez-Pascau_2009, Aykut_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, another missense at the same codon, H423Y, has been classified as pathogenic in our lab. The following publications have been ascertained in the context of this evaluation (PMID: 23618813, 16434659, 19405096, 27725636). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV003037365	SCV005684521	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-05-16	criteria provided, single submitter	clinical testing