chr14-24259769-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_000359.3(TGM1):c.919C>G(p.Arg307Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,612,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307Q) has been classified as Likely benign.
Frequency
Consequence
NM_000359.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGM1 | NM_000359.3 | c.919C>G | p.Arg307Gly | missense_variant | 6/15 | ENST00000206765.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGM1 | ENST00000206765.11 | c.919C>G | p.Arg307Gly | missense_variant | 6/15 | 1 | NM_000359.3 | P1 | |
TGM1 | ENST00000559136.1 | c.-9C>G | 5_prime_UTR_variant | 2/7 | 5 | ||||
TGM1 | ENST00000544573.5 | c.-28-1381C>G | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000276 AC: 42AN: 152026Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000153 AC: 38AN: 248966Hom.: 0 AF XY: 0.000163 AC XY: 22AN XY: 135004
GnomAD4 exome AF: 0.000231 AC: 338AN: 1460950Hom.: 0 Cov.: 32 AF XY: 0.000197 AC XY: 143AN XY: 726762
GnomAD4 genome ? AF: 0.000276 AC: 42AN: 152026Hom.: 0 Cov.: 33 AF XY: 0.000404 AC XY: 30AN XY: 74232
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 03, 2020 | NM_000359.2(TGM1):c.919C>G(R307G) is classified as pathogenic in the context of TGM1-related autosomal recessive congenital ichthyosis. Sources cited for classification include the following: PMID: 22801880, 16968736, 19212342, 19890349 and 26762237. Classification of NM_000359.2(TGM1):c.919C>G(R307G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2022 | Published functional studies demonstrate this variant is associated with decreased activity of transglutaminase 1 (Oji et al., 2006; Aufenvenne et al., 2009); This variant is associated with the following publications: (PMID: 34908195, 16968736, 23278109, 19890349, 28488422, 27025581, 26076875, 19863506, 30693114, 30609409, 31980526, 34426522, 31589614, 19212342, 31168818) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | TGM1: PM3:Very Strong, PM1, PM5, PM2:Supporting, PP1, PP4, PS3:Supporting - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 307 of the TGM1 protein (p.Arg307Gly). This variant is present in population databases (rs121918731, gnomAD 0.05%). This missense change has been observed in individuals with ichthyosis (PMID: 16968736, 19863506, 26076875, 27025581, 28403434). ClinVar contains an entry for this variant (Variation ID: 372534). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGM1 protein function. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19212342). This variant disrupts the p.Arg307 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11407995, 11511296, 19262603, 20167857, 21895619, 24419105). 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. - |
Lamellar ichthyosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 14, 2017 | The p.Arg307Gly (NM_000359.2 c.919C>G) variant in TGM1 has been reported in 6 co mpound heterozygous and 1 homozygous individuals with lamellar icthyosis related conditions (self-healing collodion baby and bathing suit ichthyosis) (Oji 2006, Valquist 2010, Hackett 2010, and Pigg 2016), and segregated in 1 sibling in 1 f amily (Hackett 2010). This variant has been reported in ClinVar (Variation ID#37 2534) as pathogenic by 1 laboratory. This variant has been identified in 0.023% (14/60410) of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs121918731). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg307Gly variant may impact protein function (Aufenvenne 2009). In summary, this variant meets criteria to be classified as pathogenic for Lamel lar ichthyosis related conditions in an autosomal recessive manner based upon it s occurrence in individuals with this disease and functional evidence. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 12, 2024 | Variant summary: TGM1 c.919C>G (p.Arg307Gly) results in a non-conservative amino acid change in the encoded protein sequence. Another missense variant affecting this residue (p.Arg307Trp) has been classified as pathogenic. 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 0.00015 in 248966 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (0.00015 vs 0.0021), allowing no conclusion about variant significance. c.919C>G has been reported in the literature in multiple individuals affected with Congenital Ichthyosis (Bourrat_2012, Diociaiuti_2016), and some were compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22801880, 26762237). ClinVar contains an entry for this variant (Variation ID: 372534). 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