VCV000285418.23 - ClinVar

NM_000543.5(SMPD1):c.99G>A (p.Met33Ile)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign/Likely benign

4 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000543.5(SMPD1):c.99G>A (p.Met33Ile)

Variation ID: 285418 Accession: VCV000285418.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 6390697 (GRCh38) [ NCBI UCSC ] 11: 6411927 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Apr 13, 2025	Jan 22, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000543.5:c.99G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000534.3:p.Met33Ile	missense
NM_001007593.3:c.99G>A	NP_001007594.2:p.Met33Ile	missense
NM_001318087.2:c.99G>A	NP_001305016.1:p.Met33Ile	missense
NM_001318088.2:c.-863G>A		5 prime UTR
NM_001365135.2:c.99G>A	NP_001352064.1:p.Met33Ile	missense
NR_027400.3:n.224G>A		non-coding transcript variant
NR_134502.2:n.224G>A		non-coding transcript variant
NC_000011.10:g.6390697G>A
NC_000011.9:g.6411927G>A
NG_011780.1:g.5273G>A

... more HGVS ... less HGVS

Protein change

M33I

Other names

Canonical SPDI

NC_000011.10:6390696:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00379 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00026

The Genome Aggregation Database (gnomAD), exomes 0.00070

Exome Aggregation Consortium (ExAC) 0.00107

The Genome Aggregation Database (gnomAD) 0.00343

Trans-Omics for Precision Medicine (TOPMed) 0.00351

1000 Genomes Project 30x 0.00359

The Genome Aggregation Database (gnomAD) 0.00371

1000 Genomes Project 0.00379

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00441

Links

ClinGen: CA5852471 dbSNP: rs142178073 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SMPD1		-	-	GRCh38 GRCh37	1109	1179

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (1)	criteria provided, single submitter	Jan 21, 2016	RCV000280282.5
Niemann-Pick disease, type A Niemann-Pick disease, type B	Benign (1)	criteria provided, single submitter	Jan 22, 2025	RCV000972278.9
Niemann-Pick disease, type A	Likely benign (2)	criteria provided, single submitter	Apr 28, 2017	RCV001107112.6
SMPD1-related disorder	Benign (1)	no assertion criteria provided	Jan 10, 2023	RCV003957444.2
not provided	Likely benign (1)	criteria provided, single submitter	May 21, 2021	RCV002285303.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Jan 21, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not specified	Eurofins Ntd Llc (ga) Accession: SCV000338427.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed

Likely benign (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Niemann-Pick disease, type A	Illumina Laboratory Services, Illumina Accession: SCV001264243.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 25933391 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (May 21, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV002575573.2 First in ClinVar: Oct 01, 2022 Last updated: Mar 04, 2023	Comment: show See Variant Classification Assertion Criteria. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jan 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Niemann-Pick disease, type B Niemann-Pick disease, type A Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001119977.6 First in ClinVar: Dec 17, 2019 Last updated: Mar 04, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (May 05, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Niemann-Pick Disease, Types A/B	Natera, Inc. Accession: SCV002091655.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jan 10, 2023) N Not contributing to aggregate classification	no assertion criteria provided	SMPD1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004773429.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease.	Clark LN	PloS one	2015	PMID: 25933391
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1	-	-	-	-

Text-mined citations for rs142178073 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_000543.5(SMPD1):c.99G>A (p.Met33Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs142178073 ...