Submissions for variant NM_000543.5(SMPD1):c.1420_1421del (p.Leu474fs)

dbSNP: rs398123476

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178789	SCV000230945	pathogenic	not provided	2013-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780731	SCV000918241	pathogenic	not specified	2018-02-05	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1420_1421delCT (p.Leu474GlufsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g. p.Ala597fsX7). The variant was absent in 121390 control chromosomes. c.1420_1421delCT has been reported in the literature in individuals affected with Niemann-Pick Disease Type A in compound heterozygous and homozygous state (Hollak_2012, Manshadi_2015). These data indicate that the variant may be associated with disease. At least one publication reports that this variant leads to significant decrease of Leukocytes-ASM activity. One diagnostic laboratory classified this variant as pathogenic in 2017. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004369	SCV001163311	pathogenic	Niemann-Pick disease, type A	2024-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388422	SCV001589407	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-05-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu474Glufs*20) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 158 amino acid(s) of the SMPD1 protein. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SMPD1 protein in which other variant(s) (p.Arg542*) have been determined to be pathogenic (PMID: 22796693, 23188845, 27338287). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 93314). This variant is also known as c.1417–1418delCT. This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 25811928).
Natera, Inc.	RCV001004369	SCV002092274	pathogenic	Niemann-Pick disease, type A	2017-08-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894930	SCV004716823	pathogenic	SMPD1-related disorder	2024-01-13	no assertion criteria provided	clinical testing	The SMPD1 c.1420_1421delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu474Glufs*20). This variant (also known as c.1417_1418delCT in an alternative transcript) has been reported in the homozygous state in multiple individuals with Niemann-Pick disease type A (Table 4, Abtahi et al. 2021. PubMed ID: 34554397; Table 1, Kang et al. 2022. PubMed ID: 35617710). Additionally, this variant has been reported heterozygous with another SMPD1 variant in an individual with an intermediate Niemann-Pick disease type A/B (Table 1, Hollak et al. 2012. PubMed ID: 22818240). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic.