NM_000543.5(SMPD1):c.151_154del (p.Asp51fs) AND Niemann-Pick disease, type A

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 7, 2023
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:: RCV000411564.6

Allele description [Variation Report for NM_000543.5(SMPD1):c.151_154del (p.Asp51fs)]

NM_000543.5(SMPD1):c.151_154del (p.Asp51fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000543.5(SMPD1):c.151_154del (p.Asp51fs)

HGVS:

NC_000011.10:g.6390749_6390752del
NG_011780.1:g.5325_5328del
NM_000543.4(SMPD1):c.151_154delGACT
NM_000543.5:c.151_154delMANE SELECT
NM_001007593.3:c.151_154del
NM_001318087.2:c.151_154del
NM_001318088.2:c.-811_-808del
NM_001365135.2:c.151_154del
NP_000534.3:p.Asp51fs
NP_001007594.2:p.Asp51fs
NP_001305016.1:p.Asp51fs
NP_001352064.1:p.Asp51fs
NC_000011.10:g.6390749_6390752delGACT
NC_000011.9:g.6411977_6411980del
NC_000011.9:g.6411979_6411982del
NM_000543.4(SMPD1):c.151_154delGACT
NM_000543.4:c.151_154del
NM_000543.4:c.151_154delGACT
NM_000543.5:c.151_154del
NR_027400.3:n.276_279del
NR_134502.2:n.276_279del
p.Asp51Leufs

Protein change:

D51fs

Links:

dbSNP: rs1057516949

NCBI 1000 Genomes Browser:

rs1057516949

Molecular consequence:

NM_001318088.2:c.-811_-808del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000543.5:c.151_154del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001007593.3:c.151_154del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318087.2:c.151_154del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365135.2:c.151_154del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_027400.3:n.276_279del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.276_279del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Niemann-Pick disease, type A
Synonyms:: SPHINGOMYELIN LIPIDOSIS; SPHINGOMYELINASE DEFICIENCY
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
SCV000486483	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 8, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001422717	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 24718843, 25741868 Citation Link,
SCV004203220	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000486483

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Jun 8, 2016)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV001422717

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 22, 2020)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004203220

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 7, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cirrhosis and liver failure: expanding phenotype of Acid sphingomyelinase-deficient niemann-pick disease in adulthood.

Lidove O, Sedel F, Charlotte F, Froissart R, Vanier MT.

JIMD Rep. 2015;15:117-21. doi: 10.1007/8904_2014_306. Epub 2014 Apr 10.

PubMed [citation]

PMID:: 24718843
PMCID:: PMC4270874

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Counsyl, SCV000486483.2

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422717.2

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

Description

The p.Asp51LeufsTer25 variant in SMPD1 (also known as p.Asp49LeufsTer25 due to a difference in cDNA numbering) has been reported in one Cambodian individual with Niemann-Pick disease (PMID: 24718843) and has been identified in 0.006% (1/15898) of African chromosomes and 0.001% (1/112280) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516949). 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: 371029) as likely pathogenic by Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 51 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 24718843). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it will cause loss of function, the phenotype of an individual with the variant being highly specific for disease, and the low frequency of the variant in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).

#	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

From Baylor Genetics, SCV004203220.1

#	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

Last Updated: Sep 29, 2024

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