VCV000029795.8 - ClinVar

NM_001257180.2(SLC20A2):c.1802C>T (p.Ser601Leu)

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.

(4)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001257180.2(SLC20A2):c.1802C>T (p.Ser601Leu)

Variation ID: 29795 Accession: VCV000029795.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.21 8: 42417960 (GRCh38) [ NCBI UCSC ] 8: 42275478 (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 1, 2013	Jun 9, 2024	Aug 28, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_001257180.2:c.1802C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001244109.1:p.Ser601Leu	missense
NM_001257181.2:c.1802C>T	NP_001244110.1:p.Ser601Leu	missense
NM_006749.5:c.1802C>T	NP_006740.1:p.Ser601Leu	missense
NC_000008.11:g.42417960G>A
NC_000008.10:g.42275478G>A
NG_032161.1:g.126879C>T
	Q08357:p.Ser601Leu

... more HGVS ... less HGVS

Protein change

S601L

Other names

Canonical SPDI

NC_000008.11:42417959: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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA346850 UniProtKB: Q08357#VAR_067549 OMIM: 158378.0003 dbSNP: rs387906652 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.
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.
Idiopathic basal ganglia calcification 1	Pathogenic (4)	criteria provided, single submitter	Aug 28, 2019	RCV000172921.10

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 (Aug 28, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	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: SCV002768534.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: A heterozygous missense variant, NM_006749.4(SLC20A2):c.1802C>T, has been identified in exon 11 of 11 of the SLC20A2 gene. The variant is predicted to result in a … (more) A heterozygous missense variant, NM_006749.4(SLC20A2):c.1802C>T, has been identified in exon 11 of 11 of the SLC20A2 gene. The variant is predicted to result in a major amino acid change from a serine to a leucine at position 601 of the protein, NP_006740.1(SLC20A2):p.(Ser601Leu). The serine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the helical transmembrane XI functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). The variant has previously been described as pathogenic and segregated with disease in a family with familial idiopathic basal ganglia calcification (ClinVar, Wang, C., et al. (2012), Hsu, S., et al. (2013)). Functional analysis in transfected Xenopus oocyte cells demonstrated impaired phosphate uptake activity (Wang, C., et al. (2012)). A different variant in the same codon resulting in a change to a tryptophan, p.(Ser601Trp) has also been reported as pathogenic (ClinVar, Wang, C., et al. (2012)). In addition, functional studies for this variant in both human and Xenopus cell lines showed a similar impairment in phosphate transport (Wang, C., et al. (2012), Guo, X., et al. (2019)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Idiopathic basal ganglia calcification 1 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760214.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (Feb 01, 2013)	no assertion criteria provided Method: literature only	BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000043953.5 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (2) PubMed: 22327515‚ 23334463 Comment on evidence: In 2 affected members of a Chinese family with idiopathic basal ganglia calcification-1 (IBGC1; 213600), Wang et al. (2012) identified a heterozygous 1802C-T transition in … (more) In 2 affected members of a Chinese family with idiopathic basal ganglia calcification-1 (IBGC1; 213600), Wang et al. (2012) identified a heterozygous 1802C-T transition in the SLC20A2 gene, resulting in a ser601-to-leu (S601L) substitution in a highly conserved residue in transmembrane domain XI. The mutation was not found in 508 Chinese 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. Hsu et al. (2013) identified a heterozygous S601L substitution in the SLC20A2 gene in a patient (family F23) with IBGC1 who was of Ashkenazi Jewish and Russian descent. (less)
not provided (-)	no classification provided Method: literature only	Idiopathic basal ganglia calcification 1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086838.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 22327515‚ 23334463‚ 20301594 BookShelf: NBK1421 BookShelf: NBK1421

Comment:

A heterozygous missense variant, NM_006749.4(SLC20A2):c.1802C>T, has been identified in exon 11 of 11 of the SLC20A2 gene. The variant is predicted to result in a major amino acid change from a serine to a leucine at position 601 of the protein, NP_006740.1(SLC20A2):p.(Ser601Leu). The serine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the helical transmembrane XI functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). The variant has previously been described as pathogenic and segregated with disease in a family with familial idiopathic basal ganglia calcification (ClinVar, Wang, C., et al. (2012), Hsu, S., et al. (2013)). Functional analysis in transfected Xenopus oocyte cells demonstrated impaired phosphate uptake activity (Wang, C., et al. (2012)). A different variant in the same codon resulting in a change to a tryptophan, p.(Ser601Trp) has also been reported as pathogenic (ClinVar, Wang, C., et al. (2012)). In addition, functional studies for this variant in both human and Xenopus cell lines showed a similar impairment in phosphate transport (Wang, C., et al. (2012), Guo, X., et al. (2019)). Based on the information available at the time of curation, 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
Primary Familial Brain Calcification.	Adam MP	-	2017	PMID: 20301594
Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.	Hsu SC	Neurogenetics	2013	PMID: 23334463
Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis.	Wang C	Nature genetics	2012	PMID: 22327515

Text-mined citations for rs387906652 ...

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 Jun 10, 2024

ClinVar Genomic variation as it relates to human health

NM_001257180.2(SLC20A2):c.1802C>T (p.Ser601Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906652 ...