VCV001992992.3 - ClinVar

NM_000543.5(SMPD1):c.1340+2T>C

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000543.5(SMPD1):c.1340+2T>C

Variation ID: 1992992 Accession: VCV001992992.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 6393695 (GRCh38) [ NCBI UCSC ] 11: 6414925 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 28, 2024	Apr 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000543.5:c.1340+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001007593.3:c.1337+2T>C		splice donor
NM_001318087.2:c.1340+2T>C		splice donor
NM_001318088.2:c.419+2T>C		splice donor
NM_001365135.2:c.1208+2T>C		splice donor
NC_000011.10:g.6393695T>C
NC_000011.9:g.6414925T>C
NG_011780.1:g.8271T>C
NG_029615.1:g.30720A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:6393694:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SMPD1		-	-	GRCh38 GRCh37	993	1062

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Niemann-Pick disease, type A Niemann-Pick disease, type B	Likely pathogenic (1)	criteria provided, single submitter	May 11, 2022	RCV002796345.3
Niemann-Pick disease, type A	Likely pathogenic (1)	criteria provided, single submitter	Apr 5, 2023	RCV003465835.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Apr 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205514.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (May 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Niemann-Pick disease, type B Niemann-Pick disease, type A Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003201952.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 16199547‚ 12369017‚ 15221801‚ 27884455 Comment: This sequence change affects a donor splice site in intron 4 of the SMPD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 4 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 27884455). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. (less)

Comment:

This sequence change affects a donor splice site in intron 4 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 27884455). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
[Acid sphingomyelinase deficiency (Niemann-Pick disease type B) in adulthood: A retrospective multicentric study of 28 adult cases].	Lidove O	La Revue de medecine interne	2017	PMID: 27884455
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Screening of 25 Italian patients with Niemann-Pick A reveals fourteen new mutations, one common and thirteen private, in SMPD1.	Ricci V	Human mutation	2004	PMID: 15221801
The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.	Simonaro CM	American journal of human genetics	2002	PMID: 12369017

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000543.5(SMPD1):c.1340+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...