Submissions for variant NM_000543.5(SMPD1):c.340G>A (p.Val114Met)

gnomAD frequency: 0.00061  dbSNP: rs142215226

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000415941	SCV000332631	uncertain significance	not provided	2018-07-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000415941	SCV000493153	uncertain significance	not provided	2016-08-31	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626293	SCV000746952	uncertain significance	Niemann-Pick disease, type A	2017-12-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000626293	SCV000914524	uncertain significance	Niemann-Pick disease, type A	2023-05-22	criteria provided, single submitter	clinical testing	The SMPD1 c.340G>A (p.Val114Met) variant is a missense variant. This variant has been reported in one study, in which it is found in a compound heterozygous state with another missense variant in two siblings affected with acid sphingomyelinase deficiency (PMID: 22367733). The c.340G>A variant is reported at a frequency of 0.003089 in the Ashkenazi Jewish population of the Genome Aggregation Database (version 2.1.1). This variant is located in the saposin B-like domain of SMPD1 (PMID: 27725636). Based on the available evidence, the c.340G>A (p.Val114Met) variant is classified as a variant of uncertain significance for Niemann-Pick disease, type A.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801532	SCV000941309	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 114 of the SMPD1 protein (p.Val114Met). This variant is present in population databases (rs142215226, gnomAD 0.3%). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 22367733). It has also been observed to segregate with disease in related individuals. This variant is also known as V112M. ClinVar contains an entry for this variant (Variation ID: 281705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248937	SCV001422715	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Val114Met variant in SMPD1 (also known as p.Val112Met due to a difference in cDNA numbering) has been reported in at least 2 Macedonian individuals with Niemann-Pick Disease, segregated with disease in 2 affected relatives from 1 family (PMID: 22367733), and has been identified in 0.309% (32/10360) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142215226). This variant has also been reported in ClinVar (VariationID: 281705) as a VUS by EGL Genetic Diagnostics, CeGaT Praxis fuer Humangenetik Tuebingen, Shahid Beheshti University of Medical Sciences, and Illumina Clinical Services Laboratory. The Val at position 114 is not highly conserved in mammals and evolutionary distant species, and 1 mammal (Ferret) carries a Met, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. The p.Val114Met variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 30788890). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomelinase activity being less than 10% of normal consistent with disease (PMID: 22367733). In summary, the clinical significance of the p.Val114Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP4, PM3_supporting, PM1_supporting (Richards 2015).
Genome-Nilou Lab	RCV000626293	SCV001737163	uncertain significance	Niemann-Pick disease, type A	2021-05-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000415941	SCV002009082	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000801532	SCV002050316	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-10-01	criteria provided, single submitter	clinical testing	NM_000543.4(SMPD1):c.340G>A(V114M) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. V114M has been observed in cases with relevant disease (PMID: 22367733). Functional assessments of this variant are not available in the literature. V114M has been observed in population frequency databases (gnomAD: ASJ 0.31%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.340G>A(V114M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
New York Genome Center	RCV000801532	SCV002097966	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2020-06-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000801532	SCV002814200	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-05-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519095	SCV003576758	uncertain significance	Inborn genetic diseases	2022-05-09	criteria provided, single submitter	clinical testing	The c.340G>A (p.V114M) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a G to A substitution at nucleotide position 340, causing the valine (V) at amino acid position 114 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000415941	SCV003822012	uncertain significance	not provided	2021-08-16	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000415941	SCV004099163	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	PS3_Moderate
Mayo Clinic Laboratories, Mayo Clinic	RCV000415941	SCV004225361	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488495	SCV004241904	uncertain significance	not specified	2024-08-20	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.340G>A (p.Val114Met) results in a conservative amino acid change located in the Saposin B type domain (IPR008139) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 250390 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (0.00075 vs 0.0022), allowing no conclusion about variant significance. c.340G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals (siblings) from a family affected with an early onset form of Niemann-Pick Disease Type B (example, Gucev_2013 cited in Ota_2020). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22367733, 31941852). ClinVar contains an entry for this variant (Variation ID: 281705). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000415941	SCV005191142	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001248937	SCV001462675	uncertain significance	Sphingomyelin/cholesterol lipidosis	2019-08-02	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000415941	SCV001554174	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SMPD1 p.Val113Met variant was identified in the literature in one homozygote patient of six patients with hyperprolinaemia (freq: 0.167) (Reid_2017_PMID:28255779). A case study of two siblings with Niemann-Pick Disease type B also identified the V113M variant along with a H554Y variant in the SMPD1 gene; the mother carried the V113M variant and the father carried the H554Y variant (Gucev_2013_PMID:22367733). The variant was also identified in dbSNP (ID: rs142215226), ClinVar (classified as a VUS by EGL Genetics, Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences), Cosmic (FATHMM predicted pathogenic; score=0.72) and LOVD 3.0. The variant was identified in control databases in 207 of 281774 chromosomes at a frequency of 0.000735 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 32 of 10360 chromosomes (freq: 0.003089), Other in 10 of 7204 chromosomes (freq: 0.001388), European (non-Finnish) in 136 of 128262 chromosomes (freq: 0.00106), South Asian in 12 of 30614 chromosomes (freq: 0.000392), Latino in 13 of 35426 chromosomes (freq: 0.000367) and African in 4 of 24908 chromosomes (freq: 0.000161), while the variant was not observed in the East Asian and European (Finnish) populations. The p.Val113 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004742356	SCV005366168	uncertain significance	SMPD1-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The SMPD1 c.340G>A variant is predicted to result in the amino acid substitution p.Val114Met. This variant was reported in the compound heterozygous state in two siblings with Niemann-Pick Disease type B (Gucev et al. 2013. PubMed ID: 22367733). This variant was also reported in the homozygous state in an individual with hyperprolinaemia in which causative variants in SLC25A22 were detected (Reid et al. 2017. PubMed ID: 28255779). In this homozygous patient, leucocyte sphingomyelinase activity was 0.43 which was within normal limits, indicating this variant is less likely to be pathogenic (Reid et al. 2017. PubMed ID: 28255779). This variant was also reported in 3 patients with Parkinson's disease from a large cohort study (Alcalay et al. 2019. PubMed ID: 30788890). This variant is reported in 0.31% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.