rs121918717
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000359.3(TGM1):c.968G>A(p.Arg323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,028 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323W) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.968G>A | p.Arg323Gln | missense_variant | 6/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.968G>A | p.Arg323Gln | missense_variant | 6/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000559136.1 | c.41G>A | p.Arg14Gln | missense_variant | 2/7 | 5 | |||
TGM1 | ENST00000544573.5 | c.-28-1332G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152070Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000408 AC: 10AN: 245104Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 132940
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1458958Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 725552
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152070Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74286
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:9
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 08, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Mar 28, 2024 | PS4, PM1, PM2, PM5, PP3, PP4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12484). This variant has been previously reported as causative (PMID:19241467). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 27, 1995 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 323 of the TGM1 protein (p.Arg323Gln). This variant is present in population databases (rs121918717, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 7824952, 9545389, 19241467, 23278109). It has also been observed to segregate with disease in related individuals. This variant is also known as 322Q. ClinVar contains an entry for this variant (Variation ID: 12484). 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: 9261103, 9593710). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2021 | Published functional studies demonstrate a damaging effect: marked reduction in enzyme activity (Candi et al., 1998; Herman et al., 2009); This variant is associated with the following publications: (PMID: 7824952, 9545389, 19241467, 31168818, 32105361, 31046801, 9593710, 23278109) - |
Lamellar ichthyosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 07, 2022 | Variant summary: TGM1 c.968G>A (p.Arg323Gln) 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 4.1e-05 in 245104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (4.1e-05 vs 0.0021), allowing no conclusion about variant significance. c.968G>A has been reported in the literature in at least one homozygous and multiple compound heterozygous individuals affected with Lamellar Ichthyosis, including cases of self-improving collodion ichthyosis (e.g.Huber_1995, Hennies_1998, Herman_2009, Simpson_2020, Diep_2020, Mohamad_2021). These data indicate that the variant is very likely to be associated with disease. Experimental studies examining the activity of the variant protein in vitro have found reduced cytosolic activity and markedly reduced (2-26% of normal) membrane-bound activity, indicating that the variant has a negative impact on protein function (Huber_1997, Candi_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3) or likely pathogenic (n=1). 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