rs120074124

Variant names:

• chr11-6391976-T-C
• rs120074124
• NM_000543.5:c.911T>C

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.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 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 3.84
• Publications: 25 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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 chr11-6391975-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1067199.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 2989.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.911T>C	p.Leu304Pro	missense_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.911T>C	p.Leu304Pro	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251474 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461892 Hom.: 0 Cov.: 36 AF XY: 0.0000165 AC XY: 12 AN XY: 727248

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

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

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000538 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:5

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 15, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 05, 2016

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 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. -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 14, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Apr 25, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sphingomyelin/cholesterol lipidosis Pathogenic:1 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.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

Sep 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	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.78	D
PhyloP100		3.8
PrimateAI	Uncertain	0.74	T
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	D
GERP RS		4.9
PromoterAI		-0.059	Neutral
Varity_R		0.91
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs120074124; hg19: chr11-6413206;