NM_000543.5(SMPD1):c.1091+1G>A AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 13, 2022
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:: RCV001281414.8

Allele description [Variation Report for NM_000543.5(SMPD1):c.1091+1G>A]

NM_000543.5(SMPD1):c.1091+1G>A

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.1091+1G>A

HGVS:

NC_000011.10:g.6392157G>A
NG_011780.1:g.6733G>A
NM_000543.5:c.1091+1G>AMANE SELECT
NM_001007593.3:c.1088+1G>A
NM_001318087.2:c.1091+1G>A
NM_001318088.2:c.131G>A
NM_001365135.2:c.1092G>A
NP_001305017.1:p.Gly44Asp
NP_001352064.1:p.Arg364=
NC_000011.9:g.6413387G>A
NM_000543.4:c.1091+1G>A

Protein change:

G44D

Links:

dbSNP: rs1847955457

NCBI 1000 Genomes Browser:

rs1847955457

Molecular consequence:

NM_001318088.2:c.131G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_000543.5:c.1091+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001007593.3:c.1088+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318087.2:c.1091+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001365135.2:c.1092G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV001468719	Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 30, 2020)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001576888	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 13, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 33675270, 16199547, 12369017, 15221801, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001468719

Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 30, 2020)

inherited

clinical testing

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

SCV001576888

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 13, 2022)

germline

clinical testing

PubMed (5)
[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
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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 (6)

Details of each submission

From Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital, SCV001468719.1

#	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	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001576888.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 992698). Disruption of this splice site has been observed in individual(s) with Niemann-Pick disease (PMID: 33675270). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the SMPD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801).

#	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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