rs781006633
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000359.3(TGM1):c.791G>A(p.Arg264Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,068 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000359.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.791G>A | p.Arg264Gln | missense_variant | 5/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.791G>A | p.Arg264Gln | missense_variant | 5/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000559136.1 | c.-137G>A | 5_prime_UTR_variant | 1/7 | 5 | ||||
TGM1 | ENST00000544573.5 | c.-28-1637G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251452Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135918
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 727232
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 10, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The TGM1 c.791G>A (p.Arg264Gln) missense variant has been reported in one study in which it is found in a compound heterozygous state with a frameshift variant in one patient with a moderate form of congenital ichthyosis (Oji et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.00004 in the total population of the Exome Aggregation Consortium. Functional studies in HEK293 cells demonstrated that the p.Arg264Gln variant resulted in reduced protein expression to 70% of wild type and enzyme activity of 5-13% of wild type, depending on temperature (Oji et al. 2006; Aufenvenne et al. 2009). The evidence for this variant is limited. The Arg264Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Lamellar ichthyosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2023 | Variant summary: TGM1 c.791G>A (p.Arg264Gln) results in a 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 2.8e-05 in 251452 control chromosomes (gnomAD). c.791G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Lamellar Ichthyosis, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g. Oji_2006, Hu_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in <10% of normal activity and exhibits a slight improvement in activity at decreased temperatures (approximately 15% of WT at 31C) (Aufenvenne_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19212342, 30950025, 16968736). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 264 of the TGM1 protein (p.Arg264Gln). This variant is present in population databases (rs781006633, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 16968736, 30950025). 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: 312984). 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 TGM1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19212342). This variant disrupts the p.Arg264 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16968736, 27025581, 28403434). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at