Submissions for variant NM_000543.5(SMPD1):c.996del (p.Phe333fs)

dbSNP: rs387906289

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723827	SCV000227143	pathogenic	not provided	2014-12-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003124	SCV000697420	pathogenic	Niemann-Pick disease, type A	2016-12-15	criteria provided, single submitter	clinical testing	Variant summary: The SMPD1 c.996delC (p.Phe333Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent SMPD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 31/144104 control chromosomes at a frequency of 0.0002151, which does not exceed the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361). This variant has been reported in multiple NPDA patients and has been reported as one of the founder SMPD1 Ashkenazi mutations. This variant has also been reported in patients with Parkinson disease and was suggested to possibly contribute to PD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817028	SCV000957564	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe333Serfs*52) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is present in population databases (rs772960412, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 8401540). ClinVar contains an entry for this variant (Variation ID: 2990). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000003124	SCV001193982	pathogenic	Niemann-Pick disease, type A	2019-11-11	criteria provided, single submitter	clinical testing	NM_000543.4(SMPD1):c.996delC(aka fsP330) is classified as pathogenic in the context of Niemann-Pick disease. Sources cited for classification include the following: 9266408 and 23252888. Classification of NM_000543.4(SMPD1):c.996delC(aka fsP330) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000192223	SCV001422555	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Phe333SerfsTer52 variant in SMPD1 (also known as p.Phe331SerfsTer52 due to a difference in cDNA numbering) has been reported in at least 9 individuals with Niemann-Pick disease, segregated with disease in 3 individuals from 1 family (PMID: 15877209, 9266408, 29995201, 8401540, 12369017), and has been identified in 0.129% (13/10078) of Ashkenazi Jewish chromosomes and 0.001% (1/113702) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906289). Although this variant has been seen in the general population, its frequency is consistent with the increased carrier rate in the Ashkenazi Jewish population and is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 2990) as pathogenic by Counsyl, EGL Genetic Diagnostics, GeneReviews, Integrated Genetics, and OMIM. In vitro functional studies provide some evidence that the p.Phe333Serfs variant may impact protein function (PMID: 15877209; 9266408). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 333 and leads to a premature termination codon 52 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Although this variant causes loss of function, it is pathogenic without the use of PVS1 and was used to establish whether loss of function is a mechanism of disease. The phenotype of individuals compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10%, consistent with disease (PMID: 15877209). The presence of this variant in combination with reported pathogenic or likely pathogenic variants in at least 7 individuals with Niemann-Pick disease increases the likelihood that the p.Phe333Serfs variant is pathogenic (VariationID: 198093, 2980; PMID: 15877209, 9266408, 29995201, 8401540, 12369017). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in trans with other pathogenic variants in affected individuals, in vitro functional studies, cosegregation, and the phenotype of patients with the variant being highly specific for disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3_moderate, PP1, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000723827	SCV002020762	pathogenic	not provided	2020-07-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000817028	SCV002816526	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-01-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003124	SCV004203206	pathogenic	Niemann-Pick disease, type A	2024-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000003124	SCV000023282	pathogenic	Niemann-Pick disease, type A	1993-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000192223	SCV000238490	not provided	Sphingomyelin/cholesterol lipidosis		no assertion provided	literature only	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
Counsyl	RCV000984010	SCV000677985	pathogenic	Niemann-Pick disease, type B	2015-09-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000003124	SCV002092257	pathogenic	Niemann-Pick disease, type A	2017-03-17	no assertion criteria provided	clinical testing