NM_000543.5(SMPD1):c.1546C>T (p.His516Tyr) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 13, 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:: RCV002599678.3

Allele description [Variation Report for NM_000543.5(SMPD1):c.1546C>T (p.His516Tyr)]

NM_000543.5(SMPD1):c.1546C>T (p.His516Tyr)

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.1546C>T (p.His516Tyr)

HGVS:

NC_000011.10:g.6394257C>T
NG_011780.1:g.8833C>T
NG_029615.1:g.30158G>A
NM_000543.5:c.1546C>TMANE SELECT
NM_001007593.3:c.1543C>T
NM_001318087.2:c.*39C>T
NM_001318088.2:c.625C>T
NM_001365135.2:c.1414C>T
NP_000534.3:p.His516Tyr
NP_001007594.2:p.His515Tyr
NP_001305017.1:p.His209Tyr
NP_001352064.1:p.His472Tyr
NC_000011.9:g.6415487C>T
NR_027400.3:n.1499C>T
NR_134502.2:n.1038C>T

Protein change:

H209Y

Molecular consequence:

NM_001318087.2:c.*39C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000543.5:c.1546C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1543C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1414C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1499C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.1038C>T - 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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hypothetical_protein [Candidozyma auris]
hypothetical_protein [Candidozyma auris]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003499049	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31122880, 33675270, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003499049

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 13, 2022)

germline

clinical testing

PubMed (3)
[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

Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population.

Cerón-Rodríguez M, Vázquez-Martínez ER, García-Delgado C, Ortega-Vázquez A, Valencia-Mayoral P, Ramírez-Devars L, Arias-Villegas C, Monroy-Muñoz IE, López M, Cervantes A, Cerbón M, Morán-Barroso VF.

Ann Hepatol. 2019 Jul - Aug;18(4):613-619. doi: 10.1016/j.aohep.2018.12.004. Epub 2019 May 12.

PubMed [citation]

PMID:: 31122880

Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B.

Hu J, Maegawa GHB, Zhan X, Gao X, Wang Y, Xu F, Qiu W, Han L, Gu X, Zhang H.

Hum Mutat. 2021 May;42(5):614-625. doi: 10.1002/humu.24192. Epub 2021 Mar 19.

PubMed [citation]

PMID:: 33675270

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003499049.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 516 of the SMPD1 protein (p.His516Tyr). 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. 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. This variant disrupts the p.His516 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31122880, 33675270; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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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