chr19-32864206-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
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).
Frequency
Consequence
NM_014270.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000195 AC: 49AN: 251344Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135874
GnomAD4 exome AF: 0.000238 AC: 348AN: 1461860Hom.: 0 Cov.: 34 AF XY: 0.000226 AC XY: 164AN XY: 727222
GnomAD4 genome AF: 0.000217 AC: 33AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74506
ClinVar
Submissions by phenotype
Cystinuria Pathogenic:7Uncertain:1
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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. -
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 strong, PP1 supporting -
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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:1Uncertain:3
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) -
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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at