Submissions for variant NM_000543.5(SMPD1):c.872G>A (p.Arg291His)

dbSNP: rs1803161

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000675394	SCV000227144	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694381	SCV000822824	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 291 of the SMPD1 protein (p.Arg291His). This variant is present in population databases (rs1803161, gnomAD 0.2%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12369017, 26499107, 30795770). This variant is also known as R289H. ClinVar contains an entry for this variant (Variation ID: 195085). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV000694381	SCV000894646	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780734	SCV000918244	uncertain significance	not specified	2024-08-01	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.872G>A (p.Arg291His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251420 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is similar to the expected frequency for a pathogenic variant in SMPD1 causing Niemann-Pick disease type B (0.0022 vs 0.0022), allowing no conclusion about variant significance. c.872G>A has been reported in the literature in individuals affected with Niemann-Pick disease type B and Parkinsons disease (Alcalay_2019, Kirkegaard_2010, Pavlu-Pereira_2005, Reunert_2016, Simonaro_2002, Zampieri_2015, Lipinski_2019). Due to the relatively high frequency of this variant in controls, interpretation of its presence in patients is unclear. Fibroblasts from patients with this variant along with a pathogenic variant had ASM enzyme activity which varied between 10-50% of wild-type (Pavlu-Pereira_2005, Kirkegaard_2010), however the variant was not tested in isolation. The following publications have been ascertained in the context of this evaluation (PMID: 30788890, 28590786, 20111001, 30795770, 15877209, 26981555, 12369017, 26499107). ClinVar contains an entry for this variant (Variation ID: 195085). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Illumina Laboratory Services, Illumina	RCV001004581	SCV001261320	uncertain significance	Niemann-Pick disease, type A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248929	SCV001422703	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Arg291His variant in SMPD1 (also known as p.Arg289His due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 29555840, 15877209, 12369017, 12369017, 20111001, 30795770) and has been identified in 0.223% (288/129142) of European (non-Finnish) chromosomes, 0.076% (19/24968) of African chromosomes, and 0.020% (5/25108) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1803161). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 1 affected homozygote and in combination with reported pathogenic or likely pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg291His variant is pathogenic (VariationID: 2994, 550112; PMID: 29555840, 20111001, 15877209). In summary, the clinical significance of the p.Arg291His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM3, PP3 (Richards 2015).
GeneDx	RCV000675394	SCV001765011	uncertain significance	not provided	2024-09-27	criteria provided, single submitter	clinical testing	Identified in patients with Niemann-Pick type B who had significant residual enzyme activity, who were also heterozygous for a second variant in SMPD1; the phase of these variants was not reported (PMID: 12369017, 15877209, 26499107, 30795770); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20111001, 15877209, 28590786, 26981555, 30788890, 29140481, 26499107, 30795770, 34426522, 38866761, 38153678, 38992987, 12369017)
Ambry Genetics	RCV002516684	SCV003685997	uncertain significance	Inborn genetic diseases	2021-10-21	criteria provided, single submitter	clinical testing	The c.872G>A (p.R291H) 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 872, causing the arginine (R) at amino acid position 291 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000675394	SCV003822016	uncertain significance	not provided	2021-10-28	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000675394	SCV004099165	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	PS3_Supporting, PM3_Supporting, PP1, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000675394	SCV000801064	uncertain significance	not provided	2018-02-21	no assertion criteria provided	clinical testing
Baylor Genetics	RCV001004581	SCV001163669	pathogenic	Niemann-Pick disease, type A		flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000675394	SCV001549265	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SMPD1 p.Arg291His variant was identified in 4 of 558 proband chromosomes (frequency: 0.0072) from individuals or families with Niemann-Pick Disease type B (Simonaro_2002_PMID:12369017; Pavlů-Pereira_2005_PMID:15877209; Reunert_2015_PMID:26981555; Zampieri_2016_PMID:26499107). The variant was identified in dbSNP (ID: rs1803161) and ClinVar (classified as uncertain significance by Invitae, EGL Genetics, Fulgent Genetics, Integrated Genetics and Mayo Clinic Genetic Testing). The variant was identified in control databases in 325 of 282810 chromosomes at a frequency of 0.001149 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 288 of 129142 chromosomes (freq: 0.00223), Other in 7 of 7224 chromosomes (freq: 0.000969), African in 19 of 24968 chromosomes (freq: 0.000761), European (Finnish) in 5 of 25108 chromosomes (freq: 0.000199), Latino in 5 of 35434 chromosomes (freq: 0.000141) and Ashkenazi Jewish in 1 of 10366 chromosomes (freq: 0.000096), but was not observed in the East Asian or South Asian populations. The p.Arg291 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.
Natera, Inc.	RCV001004581	SCV002092250	uncertain significance	Niemann-Pick disease, type A	2020-12-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917628	SCV004734116	uncertain significance	SMPD1-related disorder	2023-11-01	no assertion criteria provided	clinical testing	The SMPD1 c.872G>A variant is predicted to result in the amino acid substitution p.Arg291His. This variant has been documented in the compound heterozygous state in at least two individuals thought to have Niemann-Pick disease; however in one case the second variant is of uncertain significance (Zampieri et al. 2016. PubMed ID: 26499107) and in the additional case(s) full genotype information was not provided (Simonaro et al. 2002. PubMed ID: 12369017, reported as R289H). This variant along with a second missense variant in this gene was also reported in one boy with Niemann-Pick disease, he also carried a homozygous 24bp duplication in CHIT1 gene (Reported as p.Arg289His in Table 1, Lipiński. 2019. PubMed ID: 30795770). This variant was also reported in one individual with Parkinson’s disease (Table S3, Robak. 2017. PubMed ID: 29140481). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.