11-6394204-G-T

Position:

chr11-6394204-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_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 Likely 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 9.37

Variant links:

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 links:

SMPD1 (HGNC:):

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a strand (size 7) in uniprot entity ASM_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

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 [Likely_pathogenic]. Clinvar id is 2980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6394204-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.1493G>T	p.Arg498Leu	missense_variant	6/6	ENST00000342245.9	NP_000534.3	P17405-1Q59EN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.1493G>T	p.Arg498Leu	missense_variant	6/6	1	NM_000543.5	ENSP00000340409.4		P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251078

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135702

show subpopulations

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 SAS 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:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000961

Alfa

AF:

0.000332

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Niemann-Pick disease, type A

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 28, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2017	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." -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -

Sphingomyelin/cholesterol lipidosis

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	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 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -

Niemann-Pick disease, type B

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Aug 10, 2015

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2024

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 A;C0268243:Niemann-Pick disease, type B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

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). 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: 1391960, 18815062). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.43

PrimateAI

Uncertain

0.64

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

GERP RS

4.7

Varity_R

0.88

gMVP

0.97

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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