NM_000543.5(SMPD1):c.1111_1112del (p.Leu371fs) AND Niemann-Pick disease, type A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 31, 2020
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:: RCV000169205.3

Allele description [Variation Report for NM_000543.5(SMPD1):c.1111_1112del (p.Leu371fs)]

NM_000543.5(SMPD1):c.1111_1112del (p.Leu371fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000543.5(SMPD1):c.1111_1112del (p.Leu371fs)

HGVS:

NC_000011.10:g.6393233CT[1]
NG_011780.1:g.7809CT[1]
NG_029615.1:g.31179AG[1]
NM_000543.5:c.1111_1112delMANE SELECT
NM_001007593.3:c.1108_1109del
NM_001318087.2:c.1111_1112del
NM_001318088.2:c.190_191del
NM_001365135.2:c.1132-382_1132-381del
NP_000534.3:p.Leu371fs
NP_001007594.2:p.Leu370fs
NP_001305016.1:p.Leu371fs
NP_001305017.1:p.Leu64fs
NC_000011.9:g.6414463CT[1]
NC_000011.9:g.6414463_6414464del
NM_000543.4:c.1111_1112delCT
NR_134502.2:n.581CT[1]

Protein change:

L370fs

Links:

dbSNP: rs786204514

NCBI 1000 Genomes Browser:

rs786204514

Molecular consequence:

NM_000543.5:c.1111_1112del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001007593.3:c.1108_1109del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318087.2:c.1111_1112del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318088.2:c.190_191del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001365135.2:c.1132-382_1132-381del - intron variant - [Sequence Ontology: SO:0001627]
NR_134502.2:n.581CT[1] - 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
SCV000220458	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 26, 2014)	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 15221801, 18052040 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001431980	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 31, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26499107, 15221801 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220458

Counsyl

criteria provided, single submitter

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

Likely pathogenic
(Jun 26, 2014)

unknown

literature only

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

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

Citation Link,

SCV001431980

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 31, 2020)

germline

clinical testing

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

Citation Link

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	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Carboxyl-terminal disulfide bond of acid sphingomyelinase is critical for its secretion and enzymatic function.

Lee CY, Tamura T, Rabah N, Lee DY, Ruel I, Hafiane A, Iatan I, Nyholt D, Laporte F, Lazure C, Wada I, Krimbou L, Genest J.

Biochemistry. 2007 Dec 25;46(51):14969-78. Epub 2007 Dec 1.

PubMed [citation]

PMID:: 18052040

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.

Zampieri S, Filocamo M, Pianta A, Lualdi S, Gort L, Coll MJ, Sinnott R, Geberhiwot T, Bembi B, Dardis A.

Hum Mutat. 2016 Feb;37(2):139-47. doi: 10.1002/humu.22923. Epub 2015 Dec 1. Review.

PubMed [citation]

PMID:: 26499107

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000220458.2

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001431980.1

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

Description

Variant summary: SMPD1 c.1111_1112delCT (p.Leu371PhefsX19) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249166 control chromosomes. c.1111_1112delCT has been reported in the literature in at-least one individual affected with Niemann-Pick Disease Type A and has been subsequently cited by others (example, Ricci_2004, Zampieri_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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: Sep 29, 2024

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