rs79987078

chr19-32864206-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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 Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SLC7A9 NM_014270.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 5.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 26) in uniprot entity BAT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014270.5
• PM2: Very rare variant in population databases, with high coverage
• 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: {Likely_pathogenic=2, Pathogenic=4, Uncertain_significance=1}. Variant chr19-32864206-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A9	NM_014270.5	c.368C>T	p.Thr123Met	missense_variant	4/13	ENST00000023064.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A9	ENST00000023064.9	c.368C>T	p.Thr123Met	missense_variant	4/13	1	NM_014270.5	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152232 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251344 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135874

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 SAS 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.: 0 Cov.: 34 AF XY: 0.000226 AC XY: 164 AN XY: 727222

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74506

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystinuria Pathogenic:6 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 07, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 30, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 strong, PP1 supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2023	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. -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2021	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 the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5793). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	22
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	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.9e-12	A;A;A
PrimateAI	Benign	0.39	T
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	T
GERP RS		4.0
Varity_R		0.46
gMVP		0.76

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

Other links and lift over

dbSNP: rs79987078; hg19: chr19-33355112;