11-6394204-G-T

Variant names:

• chr11-6394204-G-T
• rs120074117
• NM_000543.5:c.1493G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000543.5(SMPD1):​c.1493G>T​(p.Arg498Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,008 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 9.37
• Publications: 35 publications found

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]

SMPD1 Gene-Disease associations (from GenCC):

• acid sphingomyelinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Niemann-Pick disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Niemann-Pick disease type A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• Niemann-Pick disease type B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr11-6394203-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 198095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 11-6394204-G-T is Pathogenic according to our data. Variant chr11-6394204-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.1493G>T	p.Arg498Leu	missense_variant	Exon 6 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.1493G>T	p.Arg498Leu	missense_variant	Exon 6 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251078 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112012

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.0000561 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:5

May 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000543.4(SMPD1):c.1493G>T(R498L, aka R496L) is classified as pathogenic in the context of Niemann-Pick disease. Sources cited for classification include the following: PMID 21502868, 18815062 and 2023926. Classification of NM_000543.4(SMPD1):c.1493G>T(R498L, aka R496L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jan 12, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SMPD1 c.1493G>T (p.Arg498Leu also known as c.1487G>T (p.Arg496Leu) variant located in the Calcineurin-like phophoesterase domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, which is supported by a functional study, Levran_1992. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 14/121136 (1/8650), which does not exceed the estimated maximal expected allele frequency for a pathogenic SMPD1 variant of 1/447. Multiple publications cite the variant to be found in homozygous and compound heterozygous patients diagnosed with both Niemann-Pick Disease type A and B (0.0022361). In addition, multiple clinical diagnostic laboratories classify the variant as pathogenic for both types as well. Therefore, the variant of interest has been classified as "pathogenic." -

Jun 28, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1493G>T (p.Arg498Leu) missense variant in the SMPD1 gene has been previously reported in multiple individuals affected with Niemann-Pick Disease Type A (Ricci et al., 2004; Levran et al., 1991). This variant is reported by GeneReviews (Wasserstein and Schuchman, 2015) to be one of three variants that account for over 90% of the cases of Niemann-Pick Disease Type A in individuals of Ashkenazi Jewish ancestry. SMPD1 is the only gene known to cause Niemann-Pick Disease Type A. Furthermore, molecular modeling suggests that the amino acid affected by this variant is near the active site of a metallophosphoesterase-like domain; an in vitro functional assay demonstrated that this variant resulted in reduced enzymatic activity, and mice with this variant also demonstrate very low SMPD1 enzymatic activity in the brain (Jones et al., 2008). This variant is absent or reported at low frequency in the population databases (Exome Sequencing Project = 0.12%%; 1000 Genomes = NA; and ExAC = 0.012%). It has also been shown to segregate with disease in one family over multiple generations (Levran et al., 1991). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP=4.68; CADD = 19.51; PolyPhen = 1.0; SIFT = 0.01). Emory Genetics Laboratory has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.1493G>T (p.Arg498Leu) as a Pathogenic variant for Niemann-Pick Disease Type A. We have confirmed this finding in our laboratory using Sanger sequencing. -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:3

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 498 of the SMPD1 protein (p.Arg498Leu). This variant is present in population databases (rs120074117, gnomAD 0.3%). This missense change has been observed in individual(s) with Niemann-Pick disease types A and B (PMID: 1391960, 1885770, 2023926). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 1391960, 1885770, 2023926). This variant is also known as R496L. ClinVar contains an entry for this variant (Variation ID: 2980). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 1391960, 18815062). For these reasons, this variant has been classified as Pathogenic. -

Aug 08, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Apr 06, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Common pathogenic variant in Ashkenazi Jewish patients with neuronopathic acid sphingomyelinase deficiency, also known as Niemann-Pick disease, type A (Levran et al., 1991); Functional studies found R498L is associated with less than 2% of wild-type enzyme activity (Jones et al., 2008); 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: 1885770, 18815062, 21228398, 2023926, 15221801, 26169695, 30153451, 21502868, 1391960, 26320887) -

Sphingomyelin/cholesterol lipidosis Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

1 of 3 common variants that accounts for more than 90% of pathogenic variants in persons of Ashkenazi Jewish ancestry with Niemann-Pick disease type-A -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg498Leu variant in SMPD1 (also known as p.Arg496Leu due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 2023926, 29995201, 15221801, 18815062) and has been identified in 0.280% (29/10346) of Ashkenazi Jewish chromosomes and 0.005% (6/128826) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074117). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role due to the increased carrier frequency of this variant in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 2980) as pathogenic by 8 submitters. Animal models in mice have shown that this variant causes Niemann-Pick disease (PMID: 18815062). In vitro functional studies provide additional evidence that the p.Arg498Leu variant may impact protein function (PMID: 18815062). 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 3 affected homozygotes and in combination with a reported pathogenic variant in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg498Leu variant is pathogenic (VariationID: 198093; PMID: 2023926, 29995201, 15221801, 18815062). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 18815062). Multiple variants in the same region as p.Arg498Cys have been reported in association with disease in ClinVar and the literature and the variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (VariationID: 167712, 198095; PMID: 18815062, 27725636; DOI: 10.1111/febs.13655). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on mouse models, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of individuals with the variant being highly specific for severe disease. ACMG/AMP Criteria applied: PM3_strong, PS3, PP3, PP4, PM1 (Richards 2015). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 29, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1493G>T (p.R498L) alteration is located in exon 6 (coding exon 6) of the SMPD1 gene. This alteration results from a G to T substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the SMPD1 c.1493G>T alteration was observed in 0.01% (36/282454) of total alleles studied, with a frequency of 0.28% (29/10346) in the Ashkenazi Jewish subpopulation. This mutation (also referred to as p.R496L) has been reported in the homozygous and compound heterozygous states in patients with SMPD1-related Niemann-Pick disease and is a common mutation in the Ashkenazi Jewish population (Levran, 1991; Ricci, 2004; Cox, 2018). Other alterations at this amino acid position have also been reported in affected patients (Simonaro, 2002; Ricci, 2004). Functional studies demonstrated reduced enzymatic activity in patient fibroblasts and transgenic mice with this mutation (Jones, 2008). The p.R498L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

SMPD1-related disorder Pathogenic:1

Jul 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMPD1 c.1493G>T variant is predicted to result in the amino acid substitution p.Arg498Leu. This variant has been reported in individuals with Niemann-Pick disease type A (referred to as R496L, Levran et al. 1991. PubMed ID: 2023926). This variant is reported to be one of three variants that account for approximately 90% of pathogenic alleles in individuals of Ashkenazi Jewish ancestry (Wasserstein and Schuchman et al. 2021. PubMed ID: 20301544). In vitro, in situ, and in vivo experimental studies indicate that this variant almost completely abolishes the enzyme activity of the SMPD1 protein (referred to as R496L, Jones et al 2008. PubMed ID: 18815062). This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, but is not observed in individuals of non-Ashkenazi Jewish ancestry. Alternate nucleotide changes affecting the same amino acid (p.Arg498Cys, p.Arg498His, and p.Arg498Pro) have been reported in individuals with Niemann-Pick disease type A (Simonaro et al. 2002. PubMed ID: 12369017; Ricci et al. 2004. PubMed ID: 15221801; Hu et al. 2021. PubMed ID: 33675270). The c.1493G>T (p.Arg498Leu) variant is interpreted as pathogenic. -

Niemann-Pick disease, type B Pathogenic:1

Aug 10, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.43	D
PhyloP100		9.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.98
MVP		0.98
MPC		0.85
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 15

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

Other links and lift over

dbSNP: rs120074117; hg19: chr11-6415434;