VCV000157588.11 - ClinVar

NM_194255.4(SLC19A1):c.80A>G (p.His27Arg)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Drug response

for methotrexate response - Efficacy

Classification is based on the expert panel submission

Mar 2021 by ClinPGx

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_194255.4(SLC19A1):c.80A>G (p.His27Arg)

Variation ID: 157588 Accession: VCV000157588.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.3 21: 45537880 (GRCh38) [ NCBI UCSC ] 21: 46957794 (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	Nov 13, 2014	Feb 23, 2026	Mar 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_194255.4:c.80A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_919231.1:p.His27Arg	missense
NM_001205206.4:c.80A>G	NP_001192135.1:p.His27Arg	missense
NM_001352510.2:c.-279A>G		5 prime UTR
NM_001352511.3:c.80A>G	NP_001339440.1:p.His27Arg	missense
NM_001352512.2:c.80A>G	NP_001339441.1:p.His27Arg	missense
NC_000021.9:g.45537880T>C
NC_000021.8:g.46957794T>C
NG_028278.2:g.30264A>G
	P41440:p.His27Arg

... more HGVS ... less HGVS

Protein change

H27R

Other names

RFC G80A

Canonical SPDI

NC_000021.9:45537879:T:C

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.

0.48862 (C)

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

1000 Genomes Project 30x 0.48626

1000 Genomes Project 0.48862

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.50932

Trans-Omics for Precision Medicine (TOPMed) 0.51246

The Genome Aggregation Database (gnomAD) 0.51413

The Genome Aggregation Database (gnomAD) 0.51696

Exome Aggregation Consortium (ExAC) 0.57697

Links

Genetic Testing Registry (GTR): GTR000619762 UniProtKB: P41440#VAR_020210 dbSNP: rs1051266 ClinGen: CA170984 Genetic Testing Registry (GTR): GTR000619758 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.
SLC19A1		-	-	GRCh38 GRCh38 GRCh37	244	1430

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.
Gastrointestinal stromal tumor	Uncertain significance (1)	no assertion criteria provided	-	RCV000144916.2
methotrexate response - Efficacy	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV001788041.5
not provided	Benign (1)	criteria provided, single submitter	Feb 3, 2026	RCV002055868.7
Lung cancer	Likely pathogenic (1)	no assertion criteria provided	-	RCV004797782.2
not specified	Benign (1)	criteria provided, single submitter	Jul 14, 2025	RCV006445515.1

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.	Expand all rows Collapse all rows 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.
drug response Drug-variant association: Efficacy (Mar 24, 2021) C Contributing to aggregate classification	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine)	methotrexate response - Efficacy Drug used for Arthritis, Rheumatoid	ClinPGx Accession: SCV002031253.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (9) PubMed: 15457444‚ 15677700‚ 17325736‚ 18322994‚ 19827168‚ 22450926‚ 26616421‚ 27992285‚ 31099054 Other databases https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1451245360 https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166155986 Comment: show PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

Benign (Jul 14, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007326872.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Comment: show BA1, BS2, BP4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Benign (Feb 03, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002361205.5 First in ClinVar: Apr 08, 2022 Last updated: Feb 23, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	Gastrointestinal Stromal Tumors	Department of Pharmacy and Biotechnology, University of Bologna Accession: SCV000187672.1 First in ClinVar: Nov 13, 2014 Last updated: Nov 13, 2014	Publications: PubMed (1) PubMed: 25227144 Observation: 1 Collection method: case-control Allele origin: germline Affected status: yes more Observation 1 Collection method: case-control Allele origin: germline Affected status: yes Number of individuals with the variant: 38 Zygosity: 7 Homozygotes, 31 Single Heterozygotes

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Lung cancer	Scientific Research Center, Shenzhen Evergreen Medical Institute Accession: SCV005046992.2 First in ClinVar: Dec 07, 2024 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 25227144 Observation: 1 Collection method: case-control Allele origin: germline Affected status: yes more Observation 1 Collection method: case-control Allele origin: germline Affected status: yes Number of individuals with the variant: 714 Clinical Features: Lung adenocarcinoma (present) Zygosity: 165 Homozygotes, 549 Single Heterozygotes Age: 37-93 years Sex: mixed Ethnicity/Population group: Chinese Geographic origin: Asia Platform type: SNP array Platform name: HiSeq Method: The genotyping of the samples submitted this time was conducted entirely using nucleic acid mass spectrometry. Testing laboratory: Shenzhen TAILORED Medical Ltd Date variant was reported to submitter: 2022-03-15

Comment:

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Membrane-Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population.	Lv S	Journal of clinical pharmacology	2019	PMID: 31099054
Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheumatoid arthritis? A systematic review and meta-analysis.	Chen Y	Pharmacogenomics	2017	PMID: 27992285
Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis.	Ghodke-Puranik Y	Pharmacogenomics	2015	PMID: 26616421
Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.	Angelini S	European journal of human genetics : EJHG	2015	PMID: 25227144
Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients.	Owen SA	The pharmacogenomics journal	2013	PMID: 22450926
Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis.	Hayashi H	Journal of clinical pharmacy and therapeutics	2009	PMID: 19827168
Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis.	James HM	The Journal of rheumatology	2008	PMID: 18322994
Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis.	Drozdzik M	The pharmacogenomics journal	2007	PMID: 17325736
Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study.	Dervieux T	Annals of the rheumatic diseases	2005	PMID: 15677700
Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis.	Dervieux T	Arthritis and rheumatism	2004	PMID: 15457444
https://www.pharmgkb.org/clinicalAnnotation/1451245360	-	-	-	-
https://www.pharmgkb.org/variant/PA166155986	-	-	-	-
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Text-mined citations for rs1051266 ...

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 Jul 15, 2026