NM_000543.5(SMPD1):c.1720T>G (p.Phe574Val) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 28, 2023
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:: RCV002959192.3

Allele description [Variation Report for NM_000543.5(SMPD1):c.1720T>G (p.Phe574Val)]

NM_000543.5(SMPD1):c.1720T>G (p.Phe574Val)

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.1720T>G (p.Phe574Val)

HGVS:

NC_000011.10:g.6394431T>G
NG_011780.1:g.9007T>G
NG_029615.1:g.29984A>C
NM_000543.5:c.1720T>GMANE SELECT
NM_001007593.3:c.1717T>G
NM_001318087.2:c.*213T>G
NM_001318088.2:c.799T>G
NM_001365135.2:c.1588T>G
NP_000534.3:p.Phe574Val
NP_001007594.2:p.Phe573Val
NP_001305017.1:p.Phe267Val
NP_001352064.1:p.Phe530Val
NC_000011.9:g.6415661T>G
NR_027400.3:n.1673T>G
NR_134502.2:n.1212T>G

Protein change:

F267V

Molecular consequence:

NM_001318087.2:c.*213T>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000543.5:c.1720T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1717T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.799T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1588T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1673T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.1212T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV003283971	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 28, 2023)	germline	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

SCV003283971

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 28, 2023)

germline

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	clinical testing

Citations

PubMed

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, SCV003283971.2

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 574 of the SMPD1 protein (p.Phe574Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2070825). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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