ClinVar Genomic variation as it relates to human health
NM_014270.5(SLC7A9):c.313G>A (p.Gly105Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014270.5(SLC7A9):c.313G>A (p.Gly105Arg)
Variation ID: 5781 Accession: VCV000005781.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.11 19: 32864261 (GRCh38) [ NCBI UCSC ] 19: 33355167 (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 Mar 8, 2017 Apr 15, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014270.5:c.313G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055085.1:p.Gly105Arg missense NM_001126335.2:c.313G>A NP_001119807.1:p.Gly105Arg missense NM_001243036.2:c.313G>A NP_001229965.1:p.Gly105Arg missense NC_000019.10:g.32864261C>T NC_000019.9:g.33355167C>T NG_008258.1:g.10517G>A P82251:p.Gly105Arg - Protein change
- G105R
- Other names
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- Canonical SPDI
- NC_000019.10:32864260: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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00017
Trans-Omics for Precision Medicine (TOPMed) 0.00020
Exome Aggregation Consortium (ExAC) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00027
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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SLC7A9 | - | - |
GRCh38 GRCh37 |
311 | 331 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2022 | RCV000006137.17 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000523825.17 |
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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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystinuria
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914836.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the SLC7A9 c.313G>A (p.Gly105Arg) variant has been identified in a homozygous state in at least eight patients with … (more)
Across a selection of the available literature, the SLC7A9 c.313G>A (p.Gly105Arg) variant has been identified in a homozygous state in at least eight patients with cystinuria, in a compound heterozygous state in four patients, in a heterozygous state in six patients, and in at least 37 additional patient alleles where zygosity is unspecified (Font et al. 2001; Font-Llitjós et al. 2005; Koulivand et al. 2015; Rhodes et al. 2015; Halbritter et al. 2015). It has also been observed in at least two patients who also carried variants in the SLC3A1 gene (Font-Llitjós et al. 2005; Rhodes et al. 2015). The p.Gly105Arg variant was absent from at least 100 control chromosomes (Font et al. 2001) and is reported at a frequency of 0.01402 in the Toscani in Italy population of the 1000 Genomes Project. Functional studies in HeLa cells showed the variant reduced protein expression and amino acid transport activity to ten percent of wild type (Font et al. 2001). The variant is located in a well-conserved residue. While cystinuria generally displays an autosomal recessive mode of inheritance, some heterozygous carriers of variants in the SLC7A9 gene have abnormal urinary amino acid patterns and an increased risk of kidney stones (Eggermann et al. 2012). Based on the collective evidence, the p.Gly105Arg variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Sep 26, 2022)
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criteria provided, single submitter
Method: research
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Cystinuria
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: COAGS
Accession: SCV002575015.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
PS3, PS4 (for AD) or PM3_VeryStrong (for AR), PP3
Number of individuals with the variant: 1
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Pathogenic
(Apr 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystinuria
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801823.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616881.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported as a single heterozygous variant in individuals with cystinuria (Font et al., 2001; Halbritter et al., 2015; Gaildrat et al., 2017); Published functional studies … (more)
Reported as a single heterozygous variant in individuals with cystinuria (Font et al., 2001; Halbritter et al., 2015; Gaildrat et al., 2017); Published functional studies demonstrate a damaging effect due to almost completely abolishing the amino acid transport activity of the protein, retaining only approximately 10% of wild-type transport activity (Font et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10471498, 11157794, 25296721, 28717662, 31589614, 33262960, 28812535, 30069816, 21677404, 26990548, 33226606) (less)
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Pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226701.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM3, PS3, PS4
Number of individuals with the variant: 2
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Pathogenic
(Nov 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystinuria
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020728.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001385883.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 105 of the SLC7A9 protein (p.Gly105Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 105 of the SLC7A9 protein (p.Gly105Arg). This variant is present in population databases (rs121908480, gnomAD 0.06%). This missense change has been observed in individuals with cystinuria (PMID: 10471498, 12036192, 16138908, 16225397, 16834950, 16838140, 19782624, 21677404, 23532419, 25296721, 28717662). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5781). 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 not expected to disrupt SLC7A9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC7A9 function (PMID: 11157794). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cystinuria
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429111.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystinuria
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002073754.1
First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022 |
Comment:
The c.313G>A;p.(Gly105Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5781; PMID: 10471498; 21677404; 28717662; … (more)
The c.313G>A;p.(Gly105Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5781; PMID: 10471498; 21677404; 28717662; 25296721; 16138908; 16838140; 19782624; 23532419; 16225397; 12036192) - PS4. The variant is present at low allele frequencies population databases (rs121908480 – gnomAD 0.001906%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 16834950) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Likely pathogenic
(Dec 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822542.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
SLC7A9: PM5, PS4:Moderate, PP1, PP3, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2005)
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no assertion criteria provided
Method: literature only
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CYSTINURIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026319.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017 |
Comment on evidence:
In North American and Italian patients with cystinuria defined as non-type I (see 220100), the International Cystinuria Consortium (1999) identified a G-to-A transition at nucleotide … (more)
In North American and Italian patients with cystinuria defined as non-type I (see 220100), the International Cystinuria Consortium (1999) identified a G-to-A transition at nucleotide 496 of the SLC7A9 gene, resulting in a gly105-to-arg substitution. Some of the patients were homozygous and others were heterozygous for the mutation. This was the most common mutation identified in North American and Italian patients as the cause of this disorder. In 1 of 32 heterozygotes with the G105R mutation, Font-Llitjos et al. (2005) found the urinary excretion of cystine and dibasic amino acids to be within the range of type I heterozygotes. In a patient with a mixed cystinuria phenotype (see 220100), Font-Llitjos et al. (2005) identified 3 mutations: compound heterozygosity for the SLC7A9 mutations G105R and Y232C (604144.0012), and an M467T substitution in the SLC3A1 gene (104614.0001). The patient had very low urine amino acid levels. Double heterozygotes in this family (G105R/+ and M467T/+) had higher urinary excretion levels than single heterozygotes (G105R/+ or M467T/+), suggesting digenic cystinuria. (less)
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Pathogenic
(Jan 23, 2019)
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no assertion criteria provided
Method: clinical testing
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Cystinuria
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449446.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This individual is heterozygous for the c.313G>A variant in the SLC7A9 gene, which results in the amino acid substitution of glycine to arginine at residue … (more)
This individual is heterozygous for the c.313G>A variant in the SLC7A9 gene, which results in the amino acid substitution of glycine to arginine at residue 105, p.(Gly105Arg). This variant has been previously described multiple times in the literature as the most common variant in SLC7A9 to cause cystinuria (OMIM #604144). Individuals heterozygous for the p.(Gly105Arg) variant has variable hyperexcretion of cystine and dibasic amino acids, consistent with an autosomal dominant mode of inheritance with variable expressivity (Font-Llitjos et al 2005 J Med Genet 42: 58-68). This variant is considered to be pathogenic according to the ACMG guidelines. (less)
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease. | Cogal AG | Kidney international reports | 2021 | PMID: 34805638 |
Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation. | Zacchia M | Journal of nephrology | 2021 | PMID: 33964006 |
Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants. | Gaildrat P | Molecular genetics & genomic medicine | 2017 | PMID: 28717662 |
Mutation analysis of SLC3A1 and SLC7A9 genes in patients with cystinuria. | Koulivand L | Urolithiasis | 2015 | PMID: 26123750 |
Clinical and genetic analysis of patients with cystinuria in the United Kingdom. | Rhodes HL | Clinical journal of the American Society of Nephrology : CJASN | 2015 | PMID: 25964309 |
Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. | Halbritter J | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25296721 |
Molecular characterization of cystinuria in south-eastern European countries. | Popovska-Jankovic K | Urolithiasis | 2013 | PMID: 23532419 |
Cystinuria AA (B): digenic inheritance with three mutations in two cystinuria genes. | Gucev Z | Journal of genetics | 2011 | PMID: 21677404 |
Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients. | Bisceglia L | Molecular genetics and metabolism | 2010 | PMID: 19782624 |
Evidence for association of SLC7A9 gene haplotypes with cystinuria manifestation in SLC7A9 mutation carriers. | Chatzikyriakidou A | Urological research | 2006 | PMID: 16838140 |
[SLC7A9 gene variation: impact of 13 frequent mutations in the etiology of cystinuria in a Spanish Mediterranean population]. | Francés F | Medicina clinica | 2006 | PMID: 16834950 |
Identification of novel cystinuria mutations and polymorphisms in SLC3A1 and SLC7A9 genes: absence of SLC7A10 gene mutations in cystinuric patients. | Chatzikyriakidou A | Genetic testing | 2005 | PMID: 16225397 |
Molecular genetic analysis of SLC3A1 and SLC7A9 genes in Czech and Slovak cystinuric patients. | Skopková Z | Annals of human genetics | 2005 | PMID: 16138908 |
New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype. | Font-Llitjós M | Journal of medical genetics | 2005 | PMID: 15635077 |
Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease. | Schmidt C | Clinical nephrology | 2002 | PMID: 12036192 |
Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria. | Font MA | Human molecular genetics | 2001 | PMID: 11157794 |
Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT. | Feliubadaló L | Nature genetics | 1999 | PMID: 10471498 |
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Text-mined citations for rs121908480 ...
HelpRecord last updated Apr 15, 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.