rs397514525

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000359.3(TGM1):c.943C>T(p.Arg315Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,980 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.999

Variant links:

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]

TGM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-24259744-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 14-24259745-G-A is Pathogenic according to our data. Variant chr14-24259745-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24259745-G-A is described in UniProt as null. Variant chr14-24259745-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3 link	c.943C>T	p.Arg315Cys	missense_variant	Exon 6 of 15	ENST00000206765.11	NP_000350.1	P22735-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGM1	ENST00000206765.11 link	c.943C>T	p.Arg315Cys	missense_variant	Exon 6 of 15	1	NM_000359.3	ENSP00000206765.6	P22735-1
TGM1	ENST00000559136.1 link	c.16C>T	p.Arg6Cys	missense_variant	Exon 2 of 7	5		ENSP00000453337.1	H0YLT9
TGM1	ENST00000544573.5 link	c.-28-1357C>T		intron_variant	Intron 2 of 8	2		ENSP00000439446.1	P22735-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246640

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133924

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459980

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1

Pathogenic:5

Apr 11, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.943C>T (p.Arg315Cys) in the TGM1 gene has been reported previously in compound heterozygous state in individuals affected with Bathing suit ichthyosis. Experimental studies have shown that this missense change affects TGM1 function (Oji et al., 2006; Aufenvenne et al., 2009). This variant is reported with the allele frequency (0.0008%) in the gnomAD. It has been submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Arginine at position 315 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg315Cys in TGM1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Sep 07, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Jul 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 39529). This missense change has been observed in individual(s) with non-harlequin congenital ichthyosis (PMID: 9261103, 9545389, 22801880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 315 of the TGM1 protein (p.Arg315Cys). Experimental studies have shown that this missense change affects TGM1 function (PMID: 19212342). For these reasons, this variant has been classified as Pathogenic. -

Aug 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: decreased enzyme activity (PMID: 19212342); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10914678, 38181929, 9261103, 22801880, 16968736, 37762949, 9545389, 19212342) -

Lamellar ichthyosis

Pathogenic:1

Jun 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGM1 c.943C>T (p.Arg315Cys) 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 8.1e-06 in 246640 control chromosomes (gnomAD). c.943C>T has been reported in the literature as a biallelic genotype in individuals affected with Congenital Ichthyosis (e.g. Huber_1997, Hennies_1998, Bourrat_2012). These data indicate that the variant is likely to be associated with disease. When transiently expressed in HEK293 cells, the variant had 13.99% relative activity at 31C and 5.59% relative activity at 37C, compared to wild-type (Aufenvenne_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19212342, 22801880, 9545389, 9261103). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.44

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0090

D;.

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.93

Loss of disorder (P = 0.0044);.;

MVP

0.98

MPC

1.1

ClinPred

0.88

GERP RS

4.9

Varity_R

0.43

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over