14-24259769-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 1.23

Genes affected

TGM1 (HGNC:11777): (transglutaminase 1) The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3' UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000359.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-24259769-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 14-24259769-G-C is Pathogenic according to our data. Variant chr14-24259769-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 372534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24259769-G-C is described in UniProt as null. Variant chr14-24259769-G-C is described in Lovd as [Pathogenic].

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: 42 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000153 AC: 38 AN: 248966 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135004

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000231 AC: 338 AN: 1460950 Hom.: 0 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 726762

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000492

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.000404 AC XY: 30 AN XY: 74232

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.0014
FATHMM_MKL	Benign	0.75	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.59	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.96	D
Vest4		0.61
MVP		0.90
MPC		0.95
ClinPred		0.21	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918731; hg19: chr14-24728975;