rs370129081

chr11-6394516-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000543.5(SMPD1):c.1805G>A(p.Arg602His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,611,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R602C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.39

Genes affected

SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6394515-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 878168.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787
• PP5: Variant 11-6394516-G-A is Pathogenic according to our data. Variant chr11-6394516-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394516-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1805G>A	p.Arg602His	missense_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1805G>A	p.Arg602His	missense_variant	6/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249502 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135054

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1459776 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 726322

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000842 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2023	- -

Sphingomyelin/cholesterol lipidosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2022	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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 23, 2020	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). -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.012	D;D
Vest4		0.63
MVP		0.98
MPC		0.89
ClinPred		0.73	D
GERP RS		5.4
Varity_R		0.46
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370129081; hg19: chr11-6415746;