ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.742G>A (p.Glu248Lys)
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.
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(4); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000543.5(SMPD1):c.742G>A (p.Glu248Lys)
Variation ID: 496823 Accession: VCV000496823.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6391807 (GRCh38) [ NCBI UCSC ] 11: 6413037 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 2, 2018 Feb 28, 2024 Nov 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.742G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Glu248Lys missense NM_001007593.3:c.739G>A NP_001007594.2:p.Glu247Lys missense NM_001318087.2:c.742G>A NP_001305016.1:p.Glu248Lys missense NM_001318088.2:c.-220G>A 5 prime UTR NM_001365135.2:c.742G>A NP_001352064.1:p.Glu248Lys missense NR_027400.3:n.867G>A non-coding transcript variant NC_000011.10:g.6391807G>A NC_000011.9:g.6413037G>A NG_011780.1:g.6383G>A - Protein change
- E248K, E247K
- Other names
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- Canonical SPDI
- NC_000011.10:6391806:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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SMPD1 | - | - |
GRCh38 GRCh37 |
970 | 1039 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2017 | RCV000591054.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2023 | RCV001385503.4 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2019 | RCV001004578.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248869.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003338674.2 |
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
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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
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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
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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. |
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Pathogenic
(Mar 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000700336.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163665.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(Apr 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429399.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Comment:
This variant was identified as homozygous
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001870420.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
A homozygous missense variant in exon 2 of the SMPD1 gene that results in the amino acid substitution of Lysine for Glutamic acid at codon … (more)
A homozygous missense variant in exon 2 of the SMPD1 gene that results in the amino acid substitution of Lysine for Glutamic acid at codon 248 was detected. The observed variant c.742G>A (p.Glu248Lys) has not been reported in the 1000 genomes and has a MAF of 0.004% in the gnomAD databases. The in silico prediction of the variant is damaging by SIFT, DANN, and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Mild global developmental delay (present) , Recurrent lower respiratory tract infections (present) , Hepatosplenomegaly (present) , Cherry red spot of the macula (present) , Blue … (more)
Mild global developmental delay (present) , Recurrent lower respiratory tract infections (present) , Hepatosplenomegaly (present) , Cherry red spot of the macula (present) , Blue nevus (present) , Thick eyebrow (present) , Generalized hypotonia (present) (less)
Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Sphingomyelin/cholesterol lipidosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422544.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Glu248Lys variant in SMPD1 (also known as p.Glu246Lys due to a difference in cDNA numbering) has been reported in 2 Italian individuals and 1 … (more)
The p.Glu248Lys variant in SMPD1 (also known as p.Glu246Lys due to a difference in cDNA numbering) has been reported in 2 Italian individuals and 1 Korean individual with Niemann-Pick disease (PMID: 15221801, 19411774) and has been identified in 0.001% (1/128306) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200763423). 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: 496823) as pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in an affected homozygote and in combination with a likely pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Glu248Lys variant is pathogenic (PMID: 15221801). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_supporting (Richards 2015). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047959.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The p.Glu248Lys variant in SMPD1 (also known as p.Glu246Lys due to a difference in cDNA numbering) has been reported in 2 Italian individuals and 1 … (more)
The p.Glu248Lys variant in SMPD1 (also known as p.Glu246Lys due to a difference in cDNA numbering) has been reported in 2 Italian individuals and 1 Korean individual with Niemann-Pick disease (Cho YU, Lee WM et al. 2009). Functional studies performed at one of the submitters lab indicates that this missense variant is expected to disrupt SMPD1 protein function. The p.Glu248Lys variant is reported with the allele frequency (0.00035%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic / likely Pathogenic and Uncertain Significance (VUS). The amino acid Glu at position 248 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu248Lys in SMPD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another het erozygous variant , the molecular diagnosis is not confirmed. (less)
Clinical Features:
Abnormal circulating lipid concentration (present) , Neurodegeneration (present)
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Pathogenic
(Nov 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV001585381.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 248 of the SMPD1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 248 of the SMPD1 protein (p.Glu248Lys). This variant is present in population databases (rs200763423, gnomAD 0.0008%). This missense change has been observed in individuals with Niemann-Pick disease (PMID: 15221801, 19411774, 33675270). This variant is also known as p.E246K. ClinVar contains an entry for this variant (Variation ID: 496823). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMPD1 protein function. This variant disrupts the p.Glu248 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8664904). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001870420.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B. | Hu J | Human mutation | 2021 | PMID: 33675270 |
[A case of a Korean adult affected by type B Niemann-Pick disease: secondary sea-blue histiocytosis and molecular characterization]. | Cho YU | The Korean journal of laboratory medicine | 2009 | PMID: 19411774 |
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 |
Identification of three novel mutations in the acid sphinogomyelinase gene of Japanese patients with Niemann-Pick disease type A and B. | Ida H | Human mutation | 1996 | PMID: 8664904 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/2332b872-71d1-427e-b43c-e36c272ddb0e | - | - | - | - |
Text-mined citations for rs200763423 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.