chr19-32864206-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP5

The NM_014270.5(SLC7A9):c.368C>T(p.Thr123Met) variant causes a missense change. The variant allele was found at a frequency of 0.000236 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T123T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SLC7A9
NM_014270.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:5

Conservation

PhyloP100: 5.44

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a helix (size 17) in uniprot entity BAT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_014270.5

PP5

Variant 19-32864206-G-A is Pathogenic according to our data. Variant chr19-32864206-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5793.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=4, Pathogenic=4}. Variant chr19-32864206-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A9	NM_014270.5 link	c.368C>T	p.Thr123Met	missense_variant	Exon 4 of 13	ENST00000023064.9	NP_055085.1	P82251

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A9	ENST00000023064.9 link	c.368C>T	p.Thr123Met	missense_variant	Exon 4 of 13	1	NM_014270.5	ENSP00000023064.3		P82251

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000195

AC:

AN:

251344

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.000380

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000187

AC:

AN:

53408

Gnomad4 NFE exome

AF:

0.000281

AC:

312

AN:

1111992

Gnomad4 Remaining exome

AF:

0.000199

AC:

AN:

60394

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

100

<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:

0.000217

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000120

AC:

0.000120192

AN:

0.000120192

Gnomad4 AMR

AF:

0.000457

AC:

0.000457218

AN:

0.000457218

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000294

AC:

0.000294031

AN:

0.000294031

Gnomad4 OTH

AF:

0.000473

AC:

0.000473485

AN:

0.000473485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000250

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:8Uncertain:2

Dec 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 22, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 10, 2025

Genetics Department, Catlab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.368C>T variant has been identified in multiple affected patients with cystinuria (PP4) and has been also found in trans configuration with a pathogenic variant (PMID:11157794;15635077) (PM3). The variant has a low frequency in the gnomAD 4.1 database (MAF= 0.0002360) (PM2). With all the available evidence, the variant is classified as likely pathogenic. -

Apr 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC7A9 c.368C>T (p.Thr123Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251344 control chromosomes (gnomAD). c.368C>T has been reported in the literature in multiple individuals affected with Cystinuria, including at least four individuals with a biallelic genotype (e.g. Font_2001, Skopkov_2005, Wong_2015, Gaildrat_2017, Alghamdi_2020, Domingo-Gallego_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33262960, 33532864, 11157794, 28717662, 16138908, 25109415). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either pathogenic (n=3)/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 07, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC7A9 c.368C>T (p.Thr123Met) variant has been reported in at least six studies and is found in a total of ten individuals including one in a homozygous state, five in a compound heterozygous state including one sibling pair, and four in a heterozygous state. (Font et al. 2001; Font-Llitjos et al. 2005; Skopkova et al. 2005; Eggermann et al. 2007; Bisceglia et al. 2010). All individuals presented with type I or non-type I phenotypes, and this variant is suggested to be associated with a mild form of the disease (Font et al. 2001). The p.Thr123Met variant was absent from 100 control chromosomes, but is reported at a frequency of 0.000378 in the Latino population of the Genome Aggregation Database. This variant is located in a transmembrane domain of the SLC7A9 protein (Font et al. 2001). Structurally, the p.Thr123Met variant is predicted to alter the hydrogen bond between the Thr123 and Thr121 residue (Martell et al. 2017). 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.Thr123Met variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 strong, PP1 supporting -

not provided

Pathogenic:1Uncertain:3

Jan 25, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in apparent homozygous state in patients with cystinuria in the literature and not observed in homozygous state in controls (PMID: 16138908, 33262960); Observed with a second SLC7A9 variant in individuals with cystinuria in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in most cases (PMID: 17539912, 19782624, 28717662, 33349102, 33532864, 25964309); Associated with a range of amino acid excretion patterns, from nearly normal to hyperexcretion of cystine, in individuals harboring this variant in the heterozygous state (PMID: 22480232, 15635077); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28717662, 28812535, 28270646, 25109415, 20981092, 11157794, 26990548, 6031738, 12234283, 12036192, 22480232, 15635077, 19782624, 31589614, 33532864, 14991253, 16834950, 33262960, 25964309, 33349102, 16138908, 17539912) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 123 of the SLC7A9 protein (p.Thr123Met). This variant is present in population databases (rs79987078, gnomAD 0.04%). This missense change has been observed in individual(s) with non-type 1 cystinuria (PMID: 16138908, 19782624, 25964309, 28717662). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5793). 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

.;N;.

REVEL

Uncertain

0.53

Sift

Benign

0.031

.;D;.

Sift4G

Uncertain

0.031

D;D;D

Polyphen

0.018

B;B;B

Vest4

0.39

MVP

0.86

MPC

0.84

ClinPred

0.13

GERP RS

4.0

Varity_R

0.46

gMVP

0.76

Mutation Taster

=2/98

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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