ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.757G>C (p.Asp253His) (rs398123479)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414126 SCV000227150 pathogenic not provided 2016-12-27 criteria provided, single submitter clinical testing
GeneDx RCV000414126 SCV000490817 pathogenic not provided 2018-02-05 criteria provided, single submitter clinical testing The D253H missense variant in the SMPD1 gene has been published in association with Niemann-Pick disease, types A/B (Desnick et al., 2010). Expression studies show that D253H is associated with less than 1% of wild-type sphingomyelin phosphodiesterase 1 enzyme activity (Desnick et al., 2010).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000175626 SCV000712581 likely pathogenic Niemann-Pick disease, type A 2017-01-24 criteria provided, single submitter clinical testing The p.Asp253His (NM_000543.4 c.757G>C) variant in SMPD1 has been reported in one compound heterozygous individual with acid sphingomyelinase deficiency (Niemann -Pick disease) (Desnick 2010) and one individual who had a child with Niemann-Pi ck disease type A, whose partner carried a pathogenic variant in the gene (ClinV ar https://www.ncbi.nlm.nih.gov/clinvar/variation/93320/ and personal communicat ion with Emory Genetics Laboratory). This variant has been identified in 1/65,79 4 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs398123479). Computational prediction tools and cons ervation analysis suggest that the p.Asp253His variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In v itro functional studies provide some evidence that the p.Asp253His variant may i mpact protein function (Desnick 2010). However, these types of assays may not ac curately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp253His vari ant is likely pathogenic for autosomal recessive acid sphingomyelinase deficienc y, based upon observation in patients and supportive population, functional and predictive data.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781868 SCV000920247 likely pathogenic not specified 2018-08-27 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.757G>C (p.Asp253His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 244684 control chromosomes (gnomAD). The variant, c.757G>C, has been reported in the literature in at-least one individual affected with Niemann-Pick Disease Type A (Desnick_2010). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Desnick_2010). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000821795 SCV000962567 likely pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2020-09-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 253 of the SMPD1 protein (p.Asp253His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs398123479, ExAC 0.002%). This variant has been observed in individuals affected with Niemann-Pick disease (PMID: 20386867, 23356216). ClinVar contains an entry for this variant (Variation ID: 93320). This variant has been reported to affect SMPD1 protein function (PMID: 20386867). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV000175626 SCV001163666 likely pathogenic Niemann-Pick disease, type A criteria provided, single submitter clinical testing
Counsyl RCV000175626 SCV001132300 likely pathogenic Niemann-Pick disease, type A 2019-07-24 no assertion criteria provided clinical testing
Counsyl RCV000984226 SCV001132301 likely pathogenic Niemann-Pick disease, type B 2019-07-24 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248868 SCV001422543 pathogenic Sphingomyelin/cholesterol lipidosis 2020-01-22 no assertion criteria provided curation The p.Asp253His variant in SMPD1 (also known as p.Asp251His due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 20386867), in 1 individual with a child with Niemann-Pick disease whose other parent also had a pathogenic variant in SMPD1 (VariationID: 93320), and has been identified in 0.004% (4/113028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123479). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 93320) as likely pathogenic by the Laboratory for Molecular Medicine and Integrated Genetics and as pathogenic by EGL Genetic Diagnostics and GeneDx. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Asp253Glu, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 15877209, 15557261, 27349982). In vitro functional studies provide some evidence that the p.Asp253His variant may impact protein function (PMID: 20386867). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was reported in combination with a reported likely pathogenic variant in an individual with Niemann-Pick disease (PMID: 20386867). The p.Asp253His 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: 27349982, 15557261). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on in vitro functional studies, the presence of another pathogenic variant in the same codon, and the residue being important for protein function and folding. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM1_supporting (Richards 2015).

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