Submissions for variant NM_000543.5(SMPD1):c.573del (p.Ser192fs)

gnomAD frequency: 0.00001  dbSNP: rs727504167

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175623	SCV000227147	pathogenic	not provided	2013-11-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586553	SCV000697418	pathogenic	Niemann-Pick disease, type A	2017-05-29	criteria provided, single submitter	clinical testing	Variant summary: The SMPD1 c.573delT (p.Ser192Alafs) variant (alternatively also known as 667delA and 567delA) 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. Truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory (e.g. c.996delC, c.1785_1786delCC, etc.). This variant is absent from 23568 control chromosomes from ExAC. This variant has been reported in several patients with Niemann-Pick disease (NPD). In homozygous state and in compound heterozygous with other severe mutations, it is found to cause type 1 NPD. It was found to be a common pathogenic variant in Israeli Arabs and Turkish patient population (Gluck_1998, Aykut_2013). On clinical laboratory in ClinVar has classified it as pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000586553	SCV000914525	pathogenic	Niemann-Pick disease, type A	2017-07-18	criteria provided, single submitter	clinical testing	The SMPD1 c.573delT (p.Ser192AlafsTer65) variant (also reported as 677delT; c.567delT; p.P189fs; fsP189) results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Ser192AlafsTer65 variant has been identified in a total of 26 individuals with acid sphingomyelinase deficiency including 20 homozygotes and one compound heterozygote with Niemann-Pick disease type A and five compound heterozygotes with Niemann-Pick disease type B, (Gluck et al. 1998; Ricci et al. 2004; Pittis et al. 2004; Desnick et al. 2010; Oyama et al. 2012; Dalal et al. 2015; Zampieri et al. 2016). Twelve of the homozygous patients are of Israeli Arab ethnicity from the lower Galilee and Samaria region, an area where consanguinity is common although none of these families were noted as consanguineous. The other eight homozygous patients, as well as at least one of the compound heterozygous patients are from Southern Italy, where it has been suggested the population is genetically similar to the Middle East. The second variant found in the compound heterozygous patients was either a missense variant (four individuals), a nonsense variant (one individual) or a frameshift variant (one individual). Two of the compound heterozygous individuals were noted to have 11% and 21.7% residual enzyme activity compared to wild type respectively (Pittis et al. 2004; Desnick et al. 2010). The p.Ser192AlafsTer65variant was absent from 50 healthy Italian controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Ser192AlafsTer65 variant is classified as pathogenic for SMPD1-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824303	SCV000965196	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser192Alafs*65) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 10694919, 20386867, 25811928, 26913189). This variant is also known as c.677delT. ClinVar contains an entry for this variant (Variation ID: 167710). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248979	SCV001422821	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Ser192AlafsTer65 variant in SMPD1 (also known as p.Ser190AlafsTer65 due to a difference in cDNA numbering) has been reported in at least 12 individuals with Niemann-Pick disease (PMID: 15241805, 15221801, 26913189, 26499107), but data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (VariationID: 167710) as pathogenic by EGL Genetic Diagnostics, Integrated Genetics, Counsyl, and Illumina Clinical Services Laboratory. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 192 and leads to a premature termination codon 65 amino acids downstream. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in 8 affected homozygotes and in combination with a reported pathogenic variant and in an individual with Niemann-Pick disease increases the likelihood that the p.Ser192Alafs variant is pathogenic (VariationID: 188840; PMID: 15241805, 15221801). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 26913189). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it will cause loss of function, the presence of the variant in affected homozygotes and compound heterozygous, and the phenotype of individuals with the variant being highly specific for disease. ACMG/AMP Criteria applied: PVS1, PM3, PP4 (Richards 2015).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000175623	SCV001446966	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000175623	SCV004042508	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SMPD1: PVS1, PM3:Strong, PM2, PP4:Moderate
Baylor Genetics	RCV000586553	SCV004203218	pathogenic	Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000983993	SCV000797023	pathogenic	Niemann-Pick disease, type B	2018-01-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000586553	SCV002091687	pathogenic	Niemann-Pick disease, type A	2017-03-16	no assertion criteria provided	clinical testing