rs141387770

Variant names:

• chr11-6391754-G-A
• rs141387770
• NM_000543.5:c.689G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP5

The NM_000543.5(SMPD1):​c.689G>A​(p.Arg230His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,611,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000066 (1 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:7
• Conservation: PhyloP100: 7.40
• Publications: 5 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: Uncertain_significance. The variant received 5 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, 6 uncertain in NM_000543.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6391753-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-6391754-G-A is Pathogenic according to our data. Variant chr11-6391754-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288072.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.689G>A	p.Arg230His	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.689G>A	p.Arg230His	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 151932 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000203 AC: 50 AN: 246700 AF XY: 0.000134

Gnomad AFR exome AF: 0.00279

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000658 AC: 96 AN: 1459878 Hom.: 1 Cov.: 37 AF XY: 0.0000633 AC XY: 46 AN XY: 726382

African (AFR) AF: 0.00209 AC: 70 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51490

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111984

Other (OTH) AF: 0.000116 AC: 7 AN: 60370

GnomAD4 genome AF: 0.000625 AC: 95 AN: 152048 Hom.: 0 Cov.: 31 AF XY: 0.000579 AC XY: 43 AN XY: 74310

African (AFR) AF: 0.00222 AC: 92 AN: 41510

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000676

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000543.4(SMPD1):c.689G>A(R230H) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. R230H has been observed in cases with relevant disease (PMID:15877209, 20386867, 26499107). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. R230H has been observed in population frequency databases (gnomAD: AFR 0.27%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.689G>A(R230H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 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 histidine, which is basic and polar, at codon 230 of the SMPD1 protein (p.Arg230His). This variant is present in population databases (rs141387770, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with ASM deficiency (PMID: 15877209, 20386867). This variant is also known as p.Arg228His. ClinVar contains an entry for this variant (Variation ID: 288072). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMPD1 protein function. This variant disrupts the p.Arg230 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17011332, 19405096, 22818240, 27338287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 11, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sphingomyelin/cholesterol lipidosis Pathogenic:1 Uncertain:2

Jan 22, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg230His variant in SMPD1 (also known as p.Arg228His due to a difference in cDNA numbering) has been reported in 3 individuals with Niemann-Pick disease (PMID: 20386867, 15877209, 26499107) and has been identified in 0.274% (67/24490) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141387770). This variant has also been reported in ClinVar (Variation ID: 288072) as a VUS by Counsyl and EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A pathogenic variant resulting in a different amino acid change at the same position, p.Arg230His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 19405096, 17011332, 23356216, 22818240, 23252888; VariationID: 370432). The phenotype of an individual heterozygous for this variant is highly specific for Niemann-Pick disease based on reduced enzyme activity detected in an assay, consistent with disease (PMID: 15877209). This variant was reported in an unknown phase with reported pathogenic variants and in individuals with Niemann-Pick disease (PMID: 20386867, 15877209). However, this variant was also found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 26499107). In summary, the clinical significance of the p.Arg230His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM5, PP3, BP2, PP4 (Richards 2015). -

Apr 29, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMPD1 c.689G>A (p.Arg230His) results in a non-conservative amino acid change of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 6.6e-05 in 1459878 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (6.6e-05 vs 0.0022), allowing no conclusion about variant significance. This variant has been reported in the presumed compound heterozygous state in multiple individuals affected with clinical features of Niemann Pick disease (example, Pavlu-Pereira_2005, Desnick_2010, Chang_2024, Hickey_2024) and as a homozygous complex allele in one individual affected with Niemann Pick disease type A (Zampieri_2016). Co-occurrences with other pathogenic variant(s) have been reported (SMPD1 1805G>A, p.R602H), providing supporting evidence for a benign role (Zampieri_2016). A different variant located at the same codon (c.688C>T, p.Arg230Cys) has been classified as Pathogenic in ClinVar, supporting a critical relevance of this residue to SMPD1 protein function. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Pavlu-Pereira_2005). The following publications have been ascertained in the context of this evaluation (PMID: 38739391, 20386867, 38992987, 15877209, 26499107). ClinVar contains an entry for this variant (Variation ID: 288072). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Niemann-Pick disease, type A Pathogenic:1 Uncertain:1

Jul 02, 2020

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Feb 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM3, PM5 -

Jun 15, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Pathogenic	0.99	D
PhyloP100		7.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.78
MVP		0.98
MPC		0.89
ClinPred		0.18	T
GERP RS		5.2
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs141387770; hg19: chr11-6412984; COSMIC: COSV54968158; COSMIC: COSV54968158;