VCV000370394.17 - ClinVar

NM_000543.5(SMPD1):c.1264-1G>T

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.

(6)

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.1264-1G>T

Variation ID: 370394 Accession: VCV000370394.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 6393616 (GRCh38) [ NCBI UCSC ] 11: 6414846 (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	Jan 6, 2017	Jun 17, 2024	Feb 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000543.5:c.1264-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001007593.3:c.1261-1G>T		splice acceptor
NM_001318087.2:c.1264-1G>T		splice acceptor
NM_001318088.2:c.343-1G>T		splice acceptor
NM_001365135.2:c.1132-1G>T		splice acceptor
NC_000011.10:g.6393616G>T
NC_000011.9:g.6414846G>T
NG_011780.1:g.8192G>T
NG_029615.1:g.30799C>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:6393615:G:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA16041484 dbSNP: rs1057516454 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	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 8, 2024	RCV000411029.8
Sphingomyelin/cholesterol lipidosis	Likely pathogenic (1)	criteria provided, single submitter	Jan 22, 2020	RCV001249050.3
Niemann-Pick disease, type A Niemann-Pick disease, type B	Likely pathogenic (1)	criteria provided, single submitter	Sep 6, 2023	RCV001379856.5

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 (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Sphingomyelin/cholesterol lipidosis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001422996.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/920e2880-0d29-4c9d-86ac-cac7c91f2ead Comment: The c.1264-1G>T variant in SMPD1 has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.001% (1/111372) of European (non-Finnish) … (more) The c.1264-1G>T variant in SMPD1 has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.001% (1/111372) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516454). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 370394) as likely pathogenic by Counsyl. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). (less)
Likely pathogenic (Feb 01, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Niemann-Pick disease, type A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000485704.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022
Likely pathogenic (Sep 06, 2023)	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: SCV001577739.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 16199547‚ 12369017‚ 15221801 Comment: 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 … (more) 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: 370394). 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 affects an acceptor splice site in intron 3 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). (less)
Likely pathogenic (Feb 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001163304.3 First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024
Likely pathogenic (Dec 12, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Niemann-Pick disease, type A Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002819471.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Publications: PubMed (1) PubMed: 35747619 Comment: Variant summary: SMPD1 c.1264-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: SMPD1 c.1264-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249036 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1264-1G>T in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Nov 30, 2017)	no assertion criteria provided Method: clinical testing	Niemann-Pick Disease, Types A/B Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002092265.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

The c.1264-1G>T variant in SMPD1 has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.001% (1/111372) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516454). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 370394) as likely pathogenic by Counsyl. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

Comment:

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: 370394). 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 affects an acceptor splice site in intron 3 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).

Comment:

Variant summary: SMPD1 c.1264-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249036 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1264-1G>T in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as likely pathogenic. Based on the evidence outlined above, the variant was 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
Genome Sequencing in the Parkinson Disease Clinic.	Hill EJ	Neurology. Genetics	2022	PMID: 35747619
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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/920e2880-0d29-4c9d-86ac-cac7c91f2ead	-	-	-	-

Text-mined citations for rs1057516454 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000543.5(SMPD1):c.1264-1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057516454 ...