VCV000336214.18 - ClinVar

NM_000341.4(SLC3A1):c.1854G>A (p.Met618Ile)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Benign(5)

6 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000341.4(SLC3A1):c.1854G>A (p.Met618Ile)

Variation ID: 336214 Accession: VCV000336214.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 44320435 (GRCh38) [ NCBI UCSC ] 2: 44547574 (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	Dec 6, 2016	Apr 13, 2025	Feb 3, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000341.4:c.1854G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000332.2:p.Met618Ile	missense
NM_001171613.2:c.*921C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001042385.2:c.*921C>T		3 prime UTR
NM_001042386.2:c.*921C>T		3 prime UTR
NM_001171603.1:c.*921C>T		3 prime UTR
NM_001171606.2:c.*921C>T		3 prime UTR
NM_001171617.1:c.*921C>T		3 prime UTR
NM_001374275.1:c.*921C>T		3 prime UTR
NM_001374276.1:c.*921C>T		3 prime UTR
NM_001374277.1:c.*921C>T		3 prime UTR
NM_006036.4:c.*921C>T		3 prime UTR
NC_000002.12:g.44320435G>A
NC_000002.11:g.44547574G>A
NG_008233.1:g.49978G>A
NG_016429.1:g.46428C>T
	Q07837:p.Met618Ile

... more HGVS ... less HGVS

Protein change

M618I

Other names

Canonical SPDI

NC_000002.12:44320434: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.

0.46086 (A)

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

1000 Genomes Project 30x 0.45425

1000 Genomes Project 0.46086

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.54490

Trans-Omics for Precision Medicine (TOPMed) 0.51593

Links

ClinGen: CA1640778 UniProtKB: Q07837#VAR_011431 dbSNP: rs698761 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.
PREPL		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	663	897
SLC3A1		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	451	685

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.
Cystinuria	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Feb 3, 2025	RCV000261712.18
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 18, 2020	RCV001672579.4

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.
Benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cystinuria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000430680.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)

Benign (Jan 18, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001883804.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021

Benign (Jul 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystinuria Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002057060.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005240657.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024

Benign (Feb 03, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystinuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001733481.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 25, 2025

Pathogenic (Feb 10, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cystinuria (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Biotechnology Lab, University of Central Punjab Accession: SCV004037440.2 First in ClinVar: Oct 07, 2023 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 37716586 Comment: A molecular and computational study performed on the Pakistani population reported this missense variant (M618I) in the SLC3A1 gene, as a pathogenic variant, by using … (more) A molecular and computational study performed on the Pakistani population reported this missense variant (M618I) in the SLC3A1 gene, as a pathogenic variant, by using the technique of Next-generation sequencing. The variant was potentially involved in causing Cystinuria by altering the structural and functional effect of the rBAT protein coded by the SLC3A1 gene. The variant was confirmed by ARMS-PCR at the population level (Zafar & Awais, 2023). (less) Number of individuals with the variant: 68 Age: 13-67 years Sex: mixed Ethnicity/Population group: Pakistani Geographic origin: Pakistan Platform type: Next-generation sequencing

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

A molecular and computational study performed on the Pakistani population reported this missense variant (M618I) in the SLC3A1 gene, as a pathogenic variant, by using the technique of Next-generation sequencing. The variant was potentially involved in causing Cystinuria by altering the structural and functional effect of the rBAT protein coded by the SLC3A1 gene. The variant was confirmed by ARMS-PCR at the population level (Zafar & Awais, 2023).

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
Molecular identification of missense variants in SLC3A1 gene; an approach leading to computer-aided drug design for cystinuria.	Zafar R	Gene	2023	PMID: 37716586

Text-mined citations for rs698761 ...

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 Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_000341.4(SLC3A1):c.1854G>A (p.Met618Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs698761 ...