VCV000553306.45 - ClinVar

NM_000543.5(SMPD1):c.581dup (p.Ala195fs)

Germline

Classification

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

Pathogenic
Pathogenic (6)

6 out of 7 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.581dup (p.Ala195fs)

Variation ID: 553306 Accession: VCV000553306.45

Type and length

Duplication, 1 bp

Location

Cytogenetic: 11p15.4 11: 6391640-6391641 (GRCh38) [ NCBI UCSC ] 11: 6412870-6412871 (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	Aug 5, 2018	Jun 20, 2026	Mar 2, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000543.5:c.581dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000534.3:p.Ala195fs	frameshift
NM_000543.5:c.581dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000543.4:c.581dupC
NM_001007593.3:c.578dup	NP_001007594.2:p.Ala194fs	frameshift
NM_001318087.2:c.581dup	NP_001305016.1:p.Ala195fs	frameshift
NM_001318088.2:c.-381dup		5 prime UTR
NM_001365135.2:c.581dup	NP_001352064.1:p.Ala195fs	frameshift
NR_027400.3:n.706dup		non-coding transcript variant
NC_000011.10:g.6391646dup
NC_000011.9:g.6412876dup
NG_011780.1:g.6222dup

... more HGVS ... less HGVS

Protein change

A194fs, A195fs

Other names

Canonical SPDI

NC_000011.10:6391640:CCCCCC:CCCCCCC

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.

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

Links

ClinGen: CA5852637 dbSNP: rs748165078 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	1152	1223

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.
Niemann-Pick disease, type A	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 2, 2026	RCV000668721.10
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 1, 2020	RCV001310952.34
Niemann-Pick disease, type A Niemann-Pick disease, type B	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2023	RCV003767966.4

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.
Pathogenic (Jan 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Niemann-Pick disease, type A	3billion Accession: SCV002059000.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:15241805 PMID:15241805 Comment: show Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000553306, PMID:15241805).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000016, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Abdominal distention (present) , Abnormality of the coagulation cascade (present) , Hepatomegaly (present) , Lethargy (present) , Seizure (present) Zygosity: 1 Homozygote Platform type: whole exome sequencing Platform name: NovaSeq

Pathogenic (Oct 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001500950.35 First in ClinVar: Mar 14, 2021 Last updated: Jun 20, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Pathogenic (Mar 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Niemann-Pick disease, type A (Autosomal recessive inheritance)	Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa Accession: SCV005038953.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Zygosity: 1 Homozygote Age: 10-19 years

Pathogenic (Mar 08, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Niemann-Pick disease, type A	Baylor Genetics Accession: SCV004205519.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Apr 26, 2023) 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: SCV004569718.3 First in ClinVar: Feb 28, 2024 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 12369017‚ 15221801‚ 33675270 Comment: show This sequence change creates a premature translational stop signal (p.Ala195Serfs*14) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 553306). For these reasons, this variant has been classified as Pathogenic. (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

Pathogenic (Mar 02, 2026) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Niemann-Pick disease, type A	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV007585784.1 First in ClinVar: May 03, 2026 Last updated: May 03, 2026	Publications: PubMed (1) PubMed: 33675270 Comment: show Variant summary: SMPD1 c.581dupC (p.Ala195SerfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.581dupC has been observed in individuals affected with Niemann-Pick disease (e.g. Hu_2021). These data indicate that the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 553306). Based on the evidence outlined above, the variant was classified as pathogenic. (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 pathogenic (Aug 24, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Niemann-Pick disease, type A	Counsyl Accession: SCV000793368.2 First in ClinVar: Aug 05, 2018 Last updated: Jun 29, 2025	Publications: PubMed (2) PubMed: 15241805‚ 16010684 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000553306, PMID:15241805).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000016, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Ala195Serfs*14) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 553306). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: SMPD1 c.581dupC (p.Ala195SerfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.581dupC has been observed in individuals affected with Niemann-Pick disease (e.g. Hu_2021). These data indicate that the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 553306). Based on the evidence outlined above, the variant was classified as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B.	Hu J	Human mutation	2021	PMID: 33675270
Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann Pick Type B disease.	Dardis A	Human mutation	2005	PMID: 16010684
Acid sphingomyelinase: identification of nine novel mutations among Italian Niemann Pick type B patients and characterization of in vivo functional in-frame start codon.	Pittis MG	Human mutation	2004	PMID: 15241805
Screening of 25 Italian patients with Niemann-Pick A reveals fourteen new mutations, one common and thirteen private, in SMPD1.	Ricci V	Human mutation	2004	PMID: 15221801
The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.	Simonaro CM	American journal of human genetics	2002	PMID: 12369017

Text-mined citations for rs748165078 ...

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 Jun 20, 2026