ClinVar Genomic variation as it relates to human health
NM_006208.3(ENPP1):c.1441C>T (p.Arg481Trp)
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
-
NM_006208.3(ENPP1):c.1441C>T (p.Arg481Trp)
Variation ID: 547983 Accession: VCV000547983.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6q23.2 6: 131872926 (GRCh38) [ NCBI UCSC ] 6: 132194066 (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 Jul 9, 2018 Apr 6, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_006208.3:c.1441C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006199.2:p.Arg481Trp missense NC_000006.12:g.131872926C>T NC_000006.11:g.132194066C>T NG_008206.1:g.69911C>T LRG_1288:g.69911C>T LRG_1288t1:c.1441C>T LRG_1288p1:p.Arg481Trp - Protein change
- R481W
- Other names
- -
- Canonical SPDI
- NC_000006.12:131872925:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
---|---|---|---|---|---|---|
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. |
|||
ENPP1 | - | - |
GRCh38 GRCh37 |
684 | 708 |
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. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, single submitter
|
Jun 28, 2017 | RCV000660584.5 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000779491.6 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 22, 2022 | RCV001157114.6 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 5, 2021 | RCV001855391.3 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jun 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Arterial calcification, generalized, of infancy, 1
Hypophosphatemic rickets, autosomal recessive, 2
Affected status: unknown
Allele origin:
maternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782696.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
|
|
Likely pathogenic
(Oct 25, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Arterial calcification, generalized, of infancy, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000916124.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ENPP1 c.1441C>T (p.Arg481Trp) missense variant has been reported in at least two studies and is found in a compound heterozygous state in two unrelated … (more)
The ENPP1 c.1441C>T (p.Arg481Trp) missense variant has been reported in at least two studies and is found in a compound heterozygous state in two unrelated individuals with generalized arterial calcification of infancy (Rutsch et al. 2003; Rutsch et al. 2008). One individual is reported to also have an affected sibling detected from prenatal diagnosis (Rutsch et al. 2008). The p.Arg481Trp variant was absent from 100 controls but is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project but this is based on one allele so the variant is presumed to be rare. Rutsch et al. (2003) performed RT-PCR studies on total RNA from one of the probands that showed that the p.Arg481Trp variant results in skipping of exon 15 which causes a frameshift. Transfection experiments in osteoblastic osteosarcoma cells showed the variant resulted in reduced activity to 30-40% of that associated with wild type ENPP1. The Arg481 residue lies in the catalytic domain of the ENPP1 protein and is conserved in human, mouse and rat ENPP1 and human ENPP3. Based on the evidence, the p.Arg481Trp variant is classified as likely pathogenic for generalized arterial calcification of infancy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypophosphatemic rickets, autosomal recessive, 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001318660.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Pathogenic
(Jan 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Arterial calcification, generalized, of infancy, 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001521013.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypophosphatemic rickets, autosomal recessive, 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521261.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense variant: previously reported to alter splicing … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:12881724). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:12881724). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000547983). A different missense change at the same codon (p.Arg481Gln) has been reported to be associated with ENPP1 related disorder (PMID: 26857895). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Bowing of the legs (present) , Hypophosphatemic rickets (present)
|
|
Pathogenic
(Nov 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002246995.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with autosomal recessive ENPP1-related conditions (PMID: 12881724, 29244957, 31826312). It has also been observed to segregate with … (more)
This missense change has been observed in individuals with autosomal recessive ENPP1-related conditions (PMID: 12881724, 29244957, 31826312). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in skipping of exon 15 and introduces a premature termination codon (PMID: 12881724). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 547983). This variant is present in population databases (rs373044722, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 481 of the ENPP1 protein (p.Arg481Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. (less)
|
|
Likely pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Arterial calcification, generalized, of infancy, 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807409.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations. | Kotwal A | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2020 | PMID: 31826312 |
Hypercementosis Associated with ENPP1 Mutations and GACI. | Thumbigere-Math V | Journal of dental research | 2018 | PMID: 29244957 |
Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification. | Ferreira CR | American journal of medical genetics. Part A | 2016 | PMID: 26857895 |
Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. | Rutsch F | Circulation. Cardiovascular genetics | 2008 | PMID: 20016754 |
Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. | Rutsch F | Nature genetics | 2003 | PMID: 12881724 |
Text-mined citations for rs373044722 ...
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.