Submissions for variant NM_000543.5(SMPD1):c.1805G>A (p.Arg602His)

gnomAD frequency: 0.00001  dbSNP: rs370129081

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169329	SCV000220664	likely pathogenic	Niemann-Pick disease, type A	2014-09-02	criteria provided, single submitter	literature only
Invitae	RCV001208506	SCV001379897	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	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 602 of the SMPD1 protein (p.Arg602His). This variant is present in population databases (rs370129081, gnomAD 0.01%). This missense change has been observed in individuals with Niemann-Pick disease (PMID: 12712061, 15241805, 27338287). This variant is also known as R600H. ClinVar contains an entry for this variant (Variation ID: 188955). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 16010684, 21098024). This variant disrupts the p.Arg602 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 15241805), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248877	SCV001422553	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-23	criteria provided, single submitter	curation	The p.Arg602His variant in SMPD1 (also known as p.Arg600His due to a difference in cDNA numbering) has been reported in at least 6 individuals with Niemann-Pick disease (PMID: 15545621, 15234149, 12712061, 26499107, 15241805) and has been identified in 0.012% (2/16240 of African chromosomes, 0.003% (1/34580) of Latino chromosomes, and 0.001% (1/113576) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 188955). 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: 188955) as likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg602His variant may impact protein function (PMID: 16010684, 21098024). 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. The presence of this variant in an affected homozygote and in combination with a reported pathogenic variants in 3 individuals with Niemann-Pick disease increases the likelihood that the p.Arg602Pro variant is pathogenic (VariationID: 198093, 188840; PMID: 15545621, 15234149, 12712061, 15241805). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg602Pro, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 16010684, 21098024, 15241805, 27725636). The p.Arg602His 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 supports pathogenicity (PMID: 21098024, 27725636). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in affected homozygotes and compound heterozygotes in trans with pathogenic variants, in vitro functional studies, the presence of other variants at the same residue, and the functional importance of the region it falls in. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PM5, PM2_supporting, PP3, PM1_supporting (Richards 2015).
Revvity Omics, Revvity	RCV001781526	SCV002020761	pathogenic	not provided	2019-08-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248877	SCV002511550	pathogenic	Sphingomyelin/cholesterol lipidosis	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1805G>A (p.Arg602His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249502 control chromosomes (gnomAD). c.1805G>A has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (e.g. Wasserstein_2004, Zampieri_2016, Hu_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 13% of normal enzymatic activity (Dardis_2005, Zampieri_2016). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169329	SCV004203215	pathogenic	Niemann-Pick disease, type A	2023-09-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169329	SCV002092300	pathogenic	Niemann-Pick disease, type A	2017-08-19	no assertion criteria provided	clinical testing