VCV002679047.2 - ClinVar

NM_000543.5(SMPD1):c.1103del (p.Phe368fs)

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.

Pathogenic/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.1103del (p.Phe368fs)

Variation ID: 2679047 Accession: VCV002679047.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 11p15.4 11: 6393226 (GRCh38) [ NCBI UCSC ] 11: 6414456 (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	Dec 30, 2023	Feb 28, 2024	May 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000543.5:c.1103del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000534.3:p.Phe368fs	frameshift
NM_001007593.3:c.1100del	NP_001007594.2:p.Phe367fs	frameshift
NM_001318087.2:c.1103del	NP_001305016.1:p.Phe368fs	frameshift
NM_001318088.2:c.182del	NP_001305017.1:p.Phe61fs	frameshift
NM_001365135.2:c.1132-390del		intron variant
NR_134502.2:n.575del		non-coding transcript variant
NC_000011.10:g.6393227del
NC_000011.9:g.6414457del
NG_011780.1:g.7803del
NG_029615.1:g.31189del

... more HGVS ... less HGVS

Protein change

F367fs, F368fs, F61fs

Other names

Canonical SPDI

NC_000011.10:6393225:TT: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.

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	992	1061

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 (1)	criteria provided, single submitter	Apr 2, 2022	RCV003466412.1
Niemann-Pick disease, type A Niemann-Pick disease, type B	Pathogenic (1)	criteria provided, single submitter	May 27, 2023	RCV003779123.2

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 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205531.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (May 27, 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: SCV004594593.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 32778503‚ 33675270‚ 12369017‚ 15221801 Comment: This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 32778503, 33675270). This variant is not present in population databases (gnomAD … (more) This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 32778503, 33675270). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe368Serfs*17) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 32778503, 33675270). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe368Serfs*17) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). For these reasons, this variant has been classified as 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
Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B.	Hu J	Human mutation	2021	PMID: 33675270
[A novel mutation in two spanish children with the Niemann Pick disease: Description of genotype, acid sphingomyelinase activity, phenotype and review].	Del Villar-Guerra P	Anales de pediatria	2021	PMID: 32778503
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 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000543.5(SMPD1):c.1103del (p.Phe368fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...