chr2-240869246-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000030.3(AGXT):c.242C>T(p.Ser81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,580 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 (★★).
Frequency
Consequence
NM_000030.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251240Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135838
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461580Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727098
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:3
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not provided Pathogenic:2
AGXT: PM3:Very Strong, PM1, PM2, PP4, PS3:Supporting -
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 81 of the AGXT protein (p.Ser81Leu). This variant is present in population databases (rs180177184, gnomAD 0.007%). This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 20564000, 24988064). ClinVar contains an entry for this variant (Variation ID: 204083). 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 AGXT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGXT function (PMID: 24990153). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.242C>T (p.S81L) alteration is located in exon 2 (coding exon 2) of the AGXT gene. This alteration results from a C to T substitution at nucleotide position 242, causing the serine (S) at amino acid position 81 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251240) total alleles studied. The highest observed frequency was 0.006% (1/16242) of African alleles. This alteration was detected in conjunction with another alteration in AGXT, in multiple individuals with AGXT-related primary hyperoxaluria (Montioli, 2014; Mandrile, 2014). This amino acid position is not well conserved in available vertebrate species. In an assay testing AGXT function, this variant showed a functionally abnormal result (Montioli, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Primary hyperoxaluria Pathogenic:1
Variant summary: AGXT c.242C>T (p.Ser81Leu) 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 1.2e-05 in 251240 control chromosomes (gnomAD). The variant, c.242C>T, has been reported in the literature in compound heterozygous individuals affected with Primary Hyperoxaluria Type 1(Montioli_2014, Williams_2009, Mandrile_2014); the variant was noted to be found on the major allele, and was described to be associated with an earlier onset of end-stage renal disease (ESRD) when it occurred in trans with a null mutation, compared to when occurring in trans with the p.G170R mutation (Montioli_2014, Mandrile_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't affect the expression level of the protein, however, it resulted in a severely decreased pyridoxal phosphate binding, with less than ~5% residual activity in the absence of PLP, while in the presence of PLP the specific activity was ~20% of the WT (Montioli_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at