rs121908484

Positions:

chr19-32843932-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_014270.5(SLC7A9):c.997C>T(p.Arg333Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R333Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SLC7A9
NM_014270.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.18

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 19-32843932-G-A is Pathogenic according to our data. Variant chr19-32843932-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-32843932-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A9	NM_014270.5 linkuse as main transcript	c.997C>T	p.Arg333Trp	missense_variant	10/13	ENST00000023064.9	NP_055085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A9	ENST00000023064.9 linkuse as main transcript	c.997C>T	p.Arg333Trp	missense_variant	10/13	1	NM_014270.5	ENSP00000023064	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251352

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000225

AC:

329

AN:

1461292

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000275

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2024	Variant summary: SLC7A9 c.997C>T (p.Arg333Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251352 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC7A9 causing Cystinuria, allowing no conclusion about variant significance. c.997C>T has been reported in the literature in multiple individuals affected with Cystinuria (example, Font_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10% of normal activity in Hela cells (Font_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11157794). ClinVar contains an entry for this variant (Variation ID: 5787). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The SLC7A9 c.997C>T (p.Arg333Trp) variant has been observed in several individuals affected with cystinuria (Halbritter J et al, Chatzikyriakidou A et al). Experimental studies have shown that this missense change abolishes SLC7A9 cysteine transport (Font MA et al). This variant is reported with the allele frequency (0.0085%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Likely Pathogenic. The amino acid Arg at position 333 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg333Trp in SLC7A9 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 10, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg333 amino acid residue in SLC7A9. Other variant(s) that disrupt this residue have been observed in individuals with SLC7A9-related conditions (PMID: 16609684, 28646536), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects SLC7A9 function (PMID: 11157794). 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 SLC7A9 protein function. ClinVar contains an entry for this variant (Variation ID: 5787). This missense change has been observed in individuals with autosomal recessive cystinuria (PMID: 11157794, 16138908, 16225397, 25296721, 25964309, 28717662). This variant is present in population databases (rs121908484, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the SLC7A9 protein (p.Arg333Trp). -

SLC7A9-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The SLC7A9 c.997C>T variant is predicted to result in the amino acid substitution p.Arg333Trp. This variant has been reported in the homozygous state in several individuals with cystinuria (ICC et al 2001. PubMed ID: 11157794; Chatzikyriakidou et al. 2005. PubMed ID: 16225397; Gaildrat et al. 2017. PubMed ID: 28717662) and the compound heterozygous state in additional individuals with cystinuria (Halbritter et al. 2014. PubMed ID: 25296721; Rhodes et al. 2015. PubMed ID: 25964309). In addition, heterozygous carriers of this variant often show a phenotype of increased urinary excretion of cysteine and dibasic amino acids, which can lead to nephrolithiasis in some individuals (OMIM #220100; ICC et al 2001. PubMed ID: 11157794). Functional studies indicate the the p.Arg333Trp variant reduces cystine transport to 10% of wild-type (ICC et al 2001. PubMed ID: 11157794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;H;H

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.6

.;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.94

MVP

0.96

MPC

1.0

ClinPred

1.0

GERP RS

3.2

Varity_R

0.92

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: 19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over