NM_000543.5(SMPD1):c.581dup (p.Ala195fs) AND Niemann-Pick disease, type A

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 2, 2026
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000668721.10

Allele description [Variation Report for NM_000543.5(SMPD1):c.581dup (p.Ala195fs)]

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

Gene:

SMPD1:sphingomyelin phosphodiesterase 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.6391646dup
NG_011780.1:g.6222dup
NM_000543.5:c.581dupMANE SELECT
NM_001007593.3:c.578dup
NM_001318087.2:c.581dup
NM_001318088.2:c.-381dup
NM_001365135.2:c.581dup
NP_000534.3:p.Ala195fs
NP_001007594.2:p.Ala194fs
NP_001305016.1:p.Ala195fs
NP_001352064.1:p.Ala195fs
NC_000011.9:g.6412870_6412871insC
NC_000011.9:g.6412876dup
NM_000543.4:c.581dupC
NM_000543.5:c.581dupCMANE SELECT
NR_027400.3:n.706dup

Protein change:

A194fs

Links:

dbSNP: rs748165078

Molecular consequence:

NM_001318088.2:c.-381dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000543.5:c.581dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001007593.3:c.578dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318087.2:c.581dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365135.2:c.581dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_027400.3:n.706dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Niemann-Pick disease, type A
Synonyms:: SPHINGOMYELIN LIPIDOSIS; SPHINGOMYELINASE DEFICIENCY; Infantile Neurovisceral ASMD (Niemann-Pick Disease Type A; NPD-A)
Identifiers:: MONDO: MONDO:0009756; MedGen: C0268242; Orphanet: 77292; OMIM: 257200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000793368	Counsyl	no assertion criteria provided	Likely pathogenic (Aug 24, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15241805, 16010684
SCV002059000	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:15241805,
SCV004205519	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005038953	Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV007585784	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 2, 2026)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	research, clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Ricci V, Guerci VI, Marçais C, Ciana G, Dardis A, Gerin F, Stroppiano M, Vanier MT, Filocamo M, Bembi B.

Hum Mutat. 2004 Aug;24(2):186-7.

PubMed [citation]

PMID:: 15241805

Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann Pick Type B disease.

Dardis A, Zampieri S, Filocamo M, Burlina A, Bembi B, Pittis MG.

Hum Mutat. 2005 Aug;26(2):164.

PubMed [citation]

PMID:: 16010684

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000793368.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002059000.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004205519.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa, SCV005038953.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV007585784.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 20, 2026

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