VCV001022704.9 - ClinVar

NM_025243.4(SLC19A3):c.1204C>G (p.Arg402Gly)

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_025243.4(SLC19A3):c.1204C>G (p.Arg402Gly)

Variation ID: 1022704 Accession: VCV001022704.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q36.3 2: 227688276 (GRCh38) [ NCBI UCSC ] 2: 228552992 (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	Mar 14, 2021	Mar 4, 2023	Jul 19, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_025243.4:c.1204C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079519.1:p.Arg402Gly	missense
NM_001371411.1:c.1204C>G	NP_001358340.1:p.Arg402Gly	missense
NM_001371412.1:c.1204C>G	NP_001358341.1:p.Arg402Gly	missense
NM_001371413.1:c.1192C>G	NP_001358342.1:p.Arg398Gly	missense
NM_001371414.1:c.1192C>G	NP_001358343.1:p.Arg398Gly	missense
NC_000002.12:g.227688276G>C
NC_000002.11:g.228552992G>C
NG_016359.1:g.34754C>G

... more HGVS ... less HGVS

Protein change

R398G, R402G

Other names

Canonical SPDI

NC_000002.12:227688275:G:C

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.

0.00020 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

dbSNP: rs150523975 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.
SLC19A3		-	-	GRCh38 GRCh37	670	695

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 provided	Uncertain significance (1)	criteria provided, single submitter	Aug 21, 2020	RCV001760408.2
Biotin-responsive basal ganglia disease	Uncertain significance (1)	criteria provided, single submitter	Jul 19, 2022	RCV001322644.6
See cases	Uncertain significance (1)	criteria provided, single submitter	Sep 22, 2019	RCV002252360.2

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 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.
Uncertain significance (Sep 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523253.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PM2, PP3 Clinical Features: Hip dislocation (present) , Dystonic disorder (present) , Choreoathetosis (present) Geographic origin: Brazil
Uncertain significance (Jul 19, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Biotin-responsive basal ganglia disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001513524.3 First in ClinVar: Mar 14, 2021 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 402 of the SLC19A3 protein (p.Arg402Gly). … (more) This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 402 of the SLC19A3 protein (p.Arg402Gly). This variant is present in population databases (rs150523975, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SLC19A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022704). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC19A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Aug 21, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001991032.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more) Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28402605) (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 402 of the SLC19A3 protein (p.Arg402Gly). This variant is present in population databases (rs150523975, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SLC19A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022704). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC19A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28402605)

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs150523975 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_025243.4(SLC19A3):c.1204C>G (p.Arg402Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150523975 ...