rs1803161
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000543.5(SMPD1):c.872G>A(p.Arg291His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,614,214 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000543.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00140 AC: 213AN: 152206Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.00110 AC: 276AN: 251420Hom.: 0 AF XY: 0.00110 AC XY: 149AN XY: 135890
GnomAD4 exome AF: 0.00183 AC: 2671AN: 1461890Hom.: 2 Cov.: 37 AF XY: 0.00180 AC XY: 1307AN XY: 727244
GnomAD4 genome AF: 0.00140 AC: 213AN: 152324Hom.: 1 Cov.: 31 AF XY: 0.00119 AC XY: 89AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:6
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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. -
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) -
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PS3_Supporting, PM3_Supporting, PP1, PP3 -
Niemann-Pick disease, type A Pathogenic:1Uncertain:2
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. -
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Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Uncertain:2
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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. -
not specified Uncertain:1
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 0.0018 in 1614214 control chromosomes, predominantly at a frequency of 0.0023 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.029 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type B phenotype (0.0022). c.872G>A has been reported in the literature in the presumed compound heterozygous or homozygous state in multiple 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, Wasserstein_2006), however it was found to segregate with disease across only 2 related individuals (Reunert_2016). Fibroblasts from patients with this variant along with a pathogenic variant had 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, 17011332). ClinVar contains an entry for this variant (Variation ID: 195085). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
SMPD1-related disorder Uncertain:1
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. -
Inborn genetic diseases Uncertain:1
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. -
Sphingomyelin/cholesterol lipidosis Uncertain:1
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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at