NM_000543.5(SMPD1):c.1557C>A (p.Tyr519Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002991766.3

Allele description [Variation Report for NM_000543.5(SMPD1):c.1557C>A (p.Tyr519Ter)]

NM_000543.5(SMPD1):c.1557C>A (p.Tyr519Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000543.5(SMPD1):c.1557C>A (p.Tyr519Ter)

HGVS:

NC_000011.10:g.6394268C>A
NG_011780.1:g.8844C>A
NG_029615.1:g.30147G>T
NM_000543.5:c.1557C>AMANE SELECT
NM_001007593.3:c.1554C>A
NM_001318087.2:c.*50C>A
NM_001318088.2:c.636C>A
NM_001365135.2:c.1425C>A
NP_000534.3:p.Tyr519Ter
NP_001007594.2:p.Tyr518Ter
NP_001305017.1:p.Tyr212Ter
NP_001352064.1:p.Tyr475Ter
NC_000011.9:g.6415498C>A
NR_027400.3:n.1510C>A
NR_134502.2:n.1049C>A

Protein change:

Y212*

Molecular consequence:

NM_001318087.2:c.*50C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NR_027400.3:n.1510C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.1049C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000543.5:c.1557C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001007593.3:c.1554C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001318088.2:c.636C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001365135.2:c.1425C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Niemann-Pick disease, type B
Identifiers:: MONDO: MONDO:0011871; MedGen: C0268243; Orphanet: 77293; OMIM: 607616

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
SCV003312560	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27338287, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003312560

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 2, 2022)

germline

clinical testing

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

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

Citations

PubMed

Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.

Ranganath P, Matta D, Bhavani GS, Wangnekar S, Jain JM, Verma IC, Kabra M, Puri RD, Danda S, Gupta N, Girisha KM, Sankar VH, Patil SJ, Ramadevi AR, Bhat M, Gowrishankar K, Mandal K, Aggarwal S, Tamhankar PM, Tilak P, Phadke SR, Dalal A.

Am J Med Genet A. 2016 Oct;170(10):2719-30. doi: 10.1002/ajmg.a.37817. Epub 2016 Jun 24.

PubMed [citation]

PMID:: 27338287

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003312560.2

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

Description

This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr519*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acid(s) of the SMPD1 protein. This variant disrupts a region of the SMPD1 protein in which other variant(s) (p.Arg602Valfs*11) have been determined to be pathogenic (PMID: 27338287; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been 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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