rs120074124

Positions:

chr11-6391976-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000543.5(SMPD1):c.911T>C(p.Leu304Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,056 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L304F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 3.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1

Transcript NM_000543.5 (SMPD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 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 chr11-6391975-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067199.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 11-6391976-T-C is Pathogenic according to our data. Variant chr11-6391976-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6391976-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5 linkuse as main transcript	c.911T>C	p.Leu304Pro	missense_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9 linkuse as main transcript	c.911T>C	p.Leu304Pro	missense_variant	2/6	1	NM_000543.5	P3	P17405-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251474

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000999

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other: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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2016	Variant summary: The c.911T>C (p.Leu304Pro, alternatively known as L302P) variant in SMPD1 gene is a missense change that alters a highly conserved nucleotide. The variant, located in the MPP_ASMase domain, is predicted to be deleterious by 5/5 in silico tools. In vitro/vivo functional studies showed that this variant caused severely reduced enzymatic activity. The variant was absent from the large and broad cohorts of the ExAC project (0/121366 chromosomes). The variant was identified in several affected individuals, including multiple homozygotes, with an established diagnosis of NPD-A. Levran (1992) reported the frequency of the variant of interest in affected individuals of Ashkenazi Jewish origin with type A NPD was greater than 20% and called it the second most common disease-causing allele in AJ. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000543.4(SMPD1):c.911T>C(L304P, aka L302P) is classified as pathogenic in the context of SMPD1-related Niemann-Pick disease. Sources cited for classification include the following: PMID 18815062, 21502868 and 1391960. Classification of NM_000543.4(SMPD1):c.911T>C(L304P, aka L302P) 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. -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 304 of the SMPD1 protein (p.Leu304Pro). This variant is present in population databases (rs120074124, gnomAD 0.04%). This missense change has been observed in individuals with Niemann-Pick type A disease (PMID: 1391960, 8401540, 10464620, 26169695). This variant is also known as p.L302P,. ClinVar contains an entry for this variant (Variation ID: 2989). 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, 26499107). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 19, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2023	Common pathogenic variant in Ashkenazi Jewish patients with Niemann-Pick disease, type A (PMID: 1391960); Expression studies show that L304P abolishes sphingomyelin phosphodiesterase 1 enzyme activity (PMID: 1391960); 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: 18815062, 8401540, 23535491, 37347058, 26320887, 36907956, 37069638, 24446175, 30788890, 26169695, 32280632, 1391960) -

Sphingomyelin/cholesterol lipidosis

Pathogenic:1Other: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, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Leu304Pro variant in SMPD1 (also known as p.Leu302Pro due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 8401540, 1391960, 18815062) and has been identified in 0.040% (4/10080) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074124). 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: 2989) as Pathogenic by Counsyl, Integrated Genetics, EGL Genetic Diagnostics, OMIM, and GeneReviews. In vitro functional studies provide some evidence that the p.Leu304Pro variant may impact protein function (PMID: 1391960, 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 at least 1 affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Leu304Pro variant is pathogenic (VariaitionID: 2990; PMID: 8401540, 1391960, 18815062). The p.Leu304Pro variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in functional domain and supports pathogenicity (PMID: 27725636, 30788890). 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. In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the in vitro functional studies, its importance in maintaining structure, and its presence in affected homozygous and compound heterozygous individuals. ACMG/AMP Criteria applied: PS3, PM3, PM1, PM2_supporting, PP3, PP4 (Richards 2015). -

Niemann-Pick disease, type B

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Counsyl

Sep 10, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

T;T;T

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.78

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0090

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.98

MVP

0.98

MPC

0.84

ClinPred

0.87

GERP RS

4.9

Varity_R

0.91

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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

Other links and lift over