19-32862521-C-T

Position:

chr19-32862521-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4

The NM_014270.5(SLC7A9):c.544G>A(p.Ala182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,613,704 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A182V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 15 hom. )

Consequence

SLC7A9
NM_014270.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:1

Conservation

PhyloP100: 1.64

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a helix (size 23) in uniprot entity BAT1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_014270.5

PP5

Variant 19-32862521-C-T is Pathogenic according to our data. Variant chr19-32862521-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5782.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=6, Uncertain_significance=1}. Variant chr19-32862521-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.013428539). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A9	NM_014270.5 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant	5/13	ENST00000023064.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A9	ENST00000023064.9 linkuse as main transcript	c.544G>A	p.Ala182Thr	missense_variant	5/13	1	NM_014270.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

360

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00262

AC:

660

AN:

251440

Hom.:

AF XY:

0.00267

AC XY:

363

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00425

AC:

6206

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00418

AC XY:

3036

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00700

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.00506

Gnomad4 OTH exome

AF:

0.00419

GnomAD4 genome

AF:

0.00236

AC:

360

AN:

152240

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.00249

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00274

AC:

333

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00491

EpiControl

AF:

0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystinuria

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 29, 2017	The SLC7A9 c.544G>A (p.Ala182Thr) variant has been reported as one of the four most common SLC7A9 variants associated with cystinuria and is associated with a mild phenotype. The p.Ala182Thr variant has been reported in six studies in which it is found in a total of at least 29 affected individuals including three in a homozygous state, two in a compound heterozygous state and 24 in a heterozygous state. One individual homozygous for the p.Ala182Thr variant also carried compound heterozygous variants in the SLC3A1 gene and four of the heterozygotes also carried a second SLC7A9 variant in cis (Feliubadalo et al. 1999; Font et al. 2001; Harnevik et al. 2003; Font-Llitjos et al. 2005; Rhodes et al. 2015; Halbritter et al. 2015). The p.Ala182Thr variant was detected in a heterozygous state in one of at least 150 control individuals and is reported at a frequency of 0.00477 in the European American population of the Exome Sequencing Project. The Ala182 residue is not highly conserved. Functional studies demonstrate that the p.Ala182Thr variant enzyme is expressed at similar levels to wild type and results in aberrant trafficking to the plasma membrane and approximately 60% of activity compared to wild type, which is consistent with its presentation with a mild phenotype (Feliubadalo et al. 1999; Font et al. 2001; Reig et al. 2002; Font-Llitjos et al. 2005). 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.Ala182Thr variant is classified as a pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -
Pathogenic, criteria provided, single submitter	research	Snyder Lab, Genetics Department, Stanford University	Jan 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Aug 30, 2019	This individual is heterozygous for the c.544G>A variant in the SLC7A9 gene, which results in the amino acid substitution of alanine to threonine at residue 182, p.(Ala182Thr). This variant has been widely reported to be disease causing in both heterozygous and compound heterozygous forms and is known to be one of the common mutations causing autosomal recessive cystinuria type I (PalaciÂn et al 2005 Physiology (Bethesda) 20: 112-124). Functional studies showed that the p.Ala182Thr substitution reduced but did not completely abolish transport activity (International Cystinuria Consortium 2001 Hum Mol Genet 10: 305-316). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PS3, PS4, PM3). -
Likely pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 29, 2014	- -
Likely pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The SLC7A9 c.544G>A (p.A182T) variant has been reported as one of the four most common SLC7A9 variants found in patients with cystinuria type B and is associated with a mild phenotype (PMID: 11157794; 12239244; 15635077; 19782624; 25109415; 25964309). -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_014270.4:c.544G>A in the SLC7A9 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Ala182Thr (NM_014270.4:c.544G>A) variant in SLC7A9 has been reported in at least 15 heterozygous, 2 homozygous, and 3 compound heterozygous individual with cystinuria type B or non-type 1 cystinuria (PMID: 10471498; 11157794; 15635077). In vitro functional studies suggest that the p.Ala182Thr variant may be a mild mutation with reduced activity (PMID: 11157794; 12234930 ). Pathogenic computational verdict because pathogenic predictions from DANN, M-CAP, MVP, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2024	The p.Ala182Thr variant in SLC7A9 has been reported in at least 15 heterozygous and >10 homozygous or compound heterozygous individual with non-type 1 cystinuria or cystinuria type B (Feliubadalo 1999 PMID: 10471498, Font 2001 PMID: 11157794, and Font-Llitjos 2005 PMID: 15635077, Rhodes 2015 PMID: 25964309, Tostivint 2017 PMID: 28646536). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 5782) and been identified in 0.4% (290/68028) of European chromosomes including 2 total homozygotes by gnomAD, (http://gnomad.broadinstitute.org v.3.1.2). In vitro functional studies suggest that the p.Ala182Thr variant may be a mild mutation with reduced activity (Font 2001 PMID: 11157794, Reig 2002 PMID: 12234930). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Pathogenic variants in SLC7A9 are associated with cystinuria type B an autosomal recessive manner, though heterozygous carriers may have an elevated risk for kidney stones and increased cysteine excretion (Font-Llitjos 2005 PMID: 15635077, Fattah 2014 PMID: 25383320). In summary, although additional studies are required to fully establish its clinical significance, the p.Ala182Thr variant is likely pathogenic for cystinuria type B in an autosomal recessive manner, though some heterozygous carriers may also be at increased risk for a milder phenotype. ACMG/AMP Criteria applied: PS4, PM3, PS3_supporting. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2023	Reported previously as a common variant associated with mild cystinuria, with both autosomal recessive and dominant inheritance described (Feliubadalo et al., 1999; Harnevik et al., 2003; Rhodes et al., 2015; Gaildrat et al., 2017; Tostivint et al., 2017); Reported with both type 1 and non-type 1 cystinuria, demonstrating reduced penetrance in heterozygotes (Font-Llitjos et al., 2005; Gaildrat et al., 2017); Suggested to be a mild variant with reduced activity that results in a trafficking defect, but no functional studies have been performed to confirm this hypothesis, and available functional studies demonstrate significant residual transporter activity comparable to wild-type (Font et al., 2001; Reig et al. 2002; Font-Llitjos et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 30487145, 25637381, 25109415, 12234930, 24123366, 11157794, 26990548, 12820697, 10471498, 15635077, 25964309, 28646536, 28717662, 25296721, 28812535, 31589614, 35923129, 35643372, 34805638, 11260385, 25777271) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 182 of the SLC7A9 protein (p.Ala182Thr). This variant is present in population databases (rs79389353, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with non-type I cystinuria or cystinuria (PMID: 10471498, 11157794, 11260385, 15635077, 25109415, 25296721, 25964309, 28646536). ClinVar contains an entry for this variant (Variation ID: 5782). 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, 12234930). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2022

The c.544G>A (p.A182T) alteration is located in exon 5 (coding exon 4) of the SLC7A9 gene. This alteration results from a G to A substitution at nucleotide position 544, causing the alanine (A) at amino acid position 182 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.26% (727/282810) total alleles studied. The highest observed frequency was 0.61% (63/10368) of Ashkenazi Jewish alleles. This alteration has been reported in multiple unrelated patients with cystinuria, and both autosomal recessive and autosomal dominant inheritance have been described (Feliubadaló, 1999; Bisceglia, 2001; Font, 2001; Font-Llitjós, 2005; Halbritter, 2015; Rhodes, 2015). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;D;D

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.76

M_CAP

Benign

0.059

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Benign

0.48

Sift4G

Benign

0.31

T;T;T

Polyphen

0.12

B;B;B

Vest4

0.23

MVP

0.88

MPC

0.30

ClinPred

0.96

GERP RS

5.5

Varity_R

0.23

gMVP

0.69

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

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

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