rs121908480

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBS2_Supporting

The NM_014270.5(SLC7A9):c.313G>A(p.Gly105Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000493 in 1,614,134 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 3 hom. )

Consequence

SLC7A9
NM_014270.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.17

Publications

31 publications found

Variant links:

Genes affected

SLC7A9 (HGNC:11067): (solute carrier family 7 member 9) This gene encodes a protein that belongs to a family of light subunits of amino acid transporters. This protein plays a role in the high-affinity and sodium-independent transport of cystine and neutral and dibasic amino acids, and appears to function in the reabsorption of cystine in the kidney tubule. Mutations in this gene cause non-type I cystinuria, a disease that leads to cystine stones in the urinary system due to impaired transport of cystine and dibasic amino acids. Alternate transcript variants, which encode the same protein, have been found for this gene. [provided by RefSeq, Jul 2011]

SLC7A9 Gene-Disease associations (from GenCC):

cystinuria
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
cystinuria type B
Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

SLC7A9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

PP5

Variant 19-32864261-C-T is Pathogenic according to our data. Variant chr19-32864261-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A9	NM_014270.5 link	c.313G>A	p.Gly105Arg	missense_variant	Exon 4 of 13	ENST00000023064.9	NP_055085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A9	ENST00000023064.9 link	c.313G>A	p.Gly105Arg	missense_variant	Exon 4 of 13	1	NM_014270.5	ENSP00000023064.3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000275

AC:

AN:

251028

AF XY:

0.000287

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000564

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000524

AC:

766

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

387

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000656

AC:

729

AN:

1111998

Other (OTH)

AF:

0.000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000190

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68006

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000354

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.00107

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:10

Dec 13, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 28, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG: PS1, PS3, PS4, PM3, PP4 -

Jan 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 23, 2019

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygotes have been reported to present with a milder phenotype (OMIM, PMID: 11157794). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (73 heterozygotes, 1 homozygote). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. More than 10 patients with Cystinuria have been reported with this variant (ClinVar, PMID: 28646536). (P) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated reduced cysteine transport (PMID: 11157794 ). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Sep 26, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PS3, PS4 (for AD) or PM3_VeryStrong (for AR), PP3 -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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-LlitjÃ³s 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-LlitjÃ³s 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. -

Apr 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:5

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC7A9: PM5, PS4:Moderate, PP1, PP3, PP4, PS3:Supporting -

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jan 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM3, PS3, PS4 -

Nov 05, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

SLC7A9-related disorder

Pathogenic:1

Sep 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SLC7A9 c.313G>A variant is predicted to result in the amino acid substitution p.Gly105Arg. This variant has been reported in the homozygous and heterozygous state in many individuals with cystinuria, non-type 1 resulting in nephrolithiasis (OMIM #220100; ICC. 1999. PubMed ID: 10471498; Font et al. 2001. PubMed ID: 11157794; Gucev et al. 2011. PubMed ID: 21677404; Halbritter et al. 2015. PubMed ID: 25296721). Functional studies indicate that the p.Gly105Arg protein variant only has 10% activity of the wild type protein which results in impaired cystine transport and a more severe urinary phenotype (Font et al. 2001. PubMed ID: 11157794). From a large cohort study, it was observed that individuals with a single pathogenic SLC7A9 variant had a mean onset of 30 years, whereas individuals with two pathogenic variants had a mean onset of 18 years (Halbritter et al. 2015. PubMed ID: 25296721). In summary, we classify the c.313G>A variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;.;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;M;M

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.9

.;D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

.;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.97

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.98

MPC

1.1

ClinPred

0.59

GERP RS

4.0

Varity_R

0.96

gMVP

0.96

Mutation Taster

=56/44

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over