PS3, PP2, PS4_Supporting, PM2
ClinVar Genomic variation as it relates to human health
NM_001257180.2(SLC20A2):c.1723G>A (p.Glu575Lys)
Germline
Classification
Help
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.
(5)
Help
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001257180.2(SLC20A2):c.1723G>A (p.Glu575Lys)
Variation ID: 29796 Accession: VCV000029796.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p11.21 8: 42428829 (GRCh38) [ NCBI UCSC ] 8: 42286347 (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 Nov 9, 2017 Oct 26, 2024 Jul 16, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001257180.2:c.1723G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001244109.1:p.Glu575Lys missense NM_001257180.1:c.1723G>A NM_001257181.2:c.1723G>A NP_001244110.1:p.Glu575Lys missense NM_006749.5:c.1723G>A NP_006740.1:p.Glu575Lys missense NC_000008.11:g.42428829C>T NC_000008.10:g.42286347C>T NG_032161.1:g.116010G>A Q08357:p.Glu575Lys - Protein change
- E575K
- Other names
- -
- Canonical SPDI
- NC_000008.11:42428828:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| SLC20A2 | - | - |
GRCh38 GRCh37 |
324 | 402 | |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 16, 2023 | RCV000022665.33 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jul 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Idiopathic basal ganglia calcification 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061506.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PP2, PS4_Supporting, PM2
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Likely pathogenic
(Nov 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Idiopathic basal ganglia calcification 1
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000891294.1
First in ClinVar: Nov 09, 2017 Last updated: Nov 09, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Idiopathic basal ganglia calcification 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005087164.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with basal ganglia calcification, idiopathic, 1 (MIM#213600). Missense variants can have both loss of function and dominant negative effects, while protein truncating variants are only known to have loss of function effects (PMID: 24209445, 23437308, 22327515, 27943094). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In two large pedigrees, mutation positive family members are all seen to have basal ganglia calcification but only some were symptomatic (PMID: 22327515). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated phosphate transporter family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by two clinical laboratories in ClinVar and observed in two individuals and one family with basal ganglia calcification in the literature (Schottlaender, 2013; PMID: 22327515, 30609140). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to significantly impair the transport of inorganic phosphate (PMID: 22327515). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 12, 2012)
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no assertion criteria provided
Method: literature only
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BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043954.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2017 |
Comment on evidence:
In 2 affected members of a Spanish family with idiopathic basal ganglia calcification-1 (IBCG1; 213600), Wang et al. (2012) identified a heterozygous 1723G-A transition in … (more)
In 2 affected members of a Spanish family with idiopathic basal ganglia calcification-1 (IBCG1; 213600), Wang et al. (2012) identified a heterozygous 1723G-A transition in the SLC20A2 gene, resulting in a glu575-to-lys (E575K) substitution in a highly conserved residue in transmembrane domain X. The mutation was not found in 288 Spanish controls, the 1000 Genomes Project, or in 2,439 control exomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in substantially impaired transport of inorganic phosphate. However, expression of the mutant protein with wildtype SLC20A2 did not result in diminished transport activity. (less)
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Likely pathogenic
(Jun 01, 2022)
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no assertion criteria provided
Method: provider interpretation
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Idiopathic basal ganglia calcification 1
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091539.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
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Comment:
Variant confirmed as disease-causing by referring clinical team
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with basal ganglia calcification, idiopathic, 1 (MIM#213600). Missense variants can have both loss of function and dominant negative effects, while protein truncating variants are only known to have loss of function effects (PMID: 24209445, 23437308, 22327515, 27943094). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In two large pedigrees, mutation positive family members are all seen to have basal ganglia calcification but only some were symptomatic (PMID: 22327515). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated phosphate transporter family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by two clinical laboratories in ClinVar and observed in two individuals and one family with basal ganglia calcification in the literature (Schottlaender, 2013; PMID: 22327515, 30609140). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to significantly impair the transport of inorganic phosphate (PMID: 22327515). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
PS3, PP2, PS4_Supporting, PM2
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with basal ganglia calcification, idiopathic, 1 (MIM#213600). Missense variants can have both loss of function and dominant negative effects, while protein truncating variants are only known to have loss of function effects (PMID: 24209445, 23437308, 22327515, 27943094). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In two large pedigrees, mutation positive family members are all seen to have basal ganglia calcification but only some were symptomatic (PMID: 22327515). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated phosphate transporter family domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by two clinical laboratories in ClinVar and observed in two individuals and one family with basal ganglia calcification in the literature (Schottlaender, 2013; PMID: 22327515, 30609140). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to significantly impair the transport of inorganic phosphate (PMID: 22327515). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of SLC20A2, PDGFRB, PDGFB, and XPR1 mutations in a large cohort of patients with primary familial brain calcification. | Guo XX | Human mutation | 2019 | PMID: 30609140 |
| Primary Brain Calcification Causal PiT2 Transport-Knockout Variants can Exert Dominant Negative Effects on Wild-Type PiT2 Transport Function in Mammalian Cells. | Larsen FT | Journal of molecular neuroscience : MN | 2017 | PMID: 27943094 |
| An update on primary familial brain calcification. | Lemos RR | International review of neurobiology | 2013 | PMID: 24209445 |
| Association between a novel mutation in SLC20A2 and familial idiopathic basal ganglia calcification. | Zhang Y | PloS one | 2013 | PMID: 23437308 |
| Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. | Wang C | Nature genetics | 2012 | PMID: 22327515 |
Text-mined citations for rs387906653 ...
HelpThese 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 Oct 27, 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.