VCV000093317.38 - ClinVar

NM_000543.5(SMPD1):c.1522G>A (p.Gly508Arg)

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.

(14)

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.

Benign

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.1522G>A (p.Gly508Arg)

Variation ID: 93317 Accession: VCV000093317.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 6394233 (GRCh38) [ NCBI UCSC ] 11: 6415463 (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	Oct 2, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000543.5:c.1522G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000534.3:p.Gly508Arg	missense
NM_001007593.3:c.1519G>A	NP_001007594.2:p.Gly507Arg	missense
NM_001318087.2:c.*15G>A		3 prime UTR
NM_001318088.2:c.601G>A	NP_001305017.1:p.Gly201Arg	missense
NM_001365135.2:c.1390G>A	NP_001352064.1:p.Gly464Arg	missense
NR_027400.3:n.1475G>A		non-coding transcript variant
NR_134502.2:n.1014G>A		non-coding transcript variant
NC_000011.10:g.6394233G>A
NC_000011.9:g.6415463G>A
NG_011780.1:g.8809G>A
NG_029615.1:g.30182C>T

... more HGVS ... less HGVS

Protein change

G508R, G201R, G464R, G507R

Other names

Canonical SPDI

NC_000011.10:6394232:G:A

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.

0.14996 (A)

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

1000 Genomes Project 0.14996

1000 Genomes Project 30x 0.15256

Trans-Omics for Precision Medicine (TOPMed) 0.18654

The Genome Aggregation Database (gnomAD), exomes 0.19138

Exome Aggregation Consortium (ExAC) 0.19174

The Genome Aggregation Database (gnomAD) 0.19762

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.19809

Links

ClinGen: CA146859 dbSNP: rs1050239 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.
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Mar 28, 2016	RCV000079195.27
Niemann-Pick disease, type A	Benign (3)	criteria provided, multiple submitters, no conflicts	Jul 1, 2021	RCV000336908.17
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Sep 5, 2016	RCV000588146.17
Niemann-Pick disease, type B	Benign (1)	criteria provided, single submitter	Jul 1, 2021	RCV001533322.10
Niemann-Pick disease, type A Niemann-Pick disease, type B	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001511035.15

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000305092.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540393.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF (less) Method: Genome/Exome Filtration
Benign (Apr 27, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111064.8 First in ClinVar: Jan 17, 2014 Last updated: Oct 02, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 Number of individuals with the variant: 82 Sex: mixed
Benign (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001749175.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Sex: mixed
Benign (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type B Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001749176.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Sex: mixed
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005323430.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Sep 05, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697413.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant Summary: The c.1522G>A in SMPD1 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 3/5 in silico tools … (more) Variant Summary: The c.1522G>A in SMPD1 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.19 (23261/121314 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.002). A reputable database/diagnostic center has classified the variant of interest as Benign. Taking together, based on the prevalence in general population, the variant was classified as Benign. (less)
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Niemann-Pick disease, type A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372942.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001859514.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 24977483)
Benign (Feb 01, 2024)	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: SCV001718210.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 28, 2024
Benign (Dec 15, 2015)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801069.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743261.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (May 06, 2017)	no assertion criteria provided Method: clinical testing	Niemann-Pick Disease, Types A/B Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002092282.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953051.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
click to load more click to collapse

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF

Comment:

Variant Summary: The c.1522G>A in SMPD1 gene is a missense change that involves the alteration of a mildly conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.19 (23261/121314 chrs tested). This frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.002). A reputable database/diagnostic center has classified the variant of interest as Benign. Taking together, based on the prevalence in general population, the variant was classified as Benign.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1	-	-	-	-

Text-mined citations for rs1050239 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000543.5(SMPD1):c.1522G>A (p.Gly508Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1050239 ...