Submissions for variant NM_000359.3(TGM1):c.877-2A>G

gnomAD frequency: 0.00027  dbSNP: rs142634031

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000290112	SCV000329548	pathogenic	not provided	2021-04-16	criteria provided, single submitter	clinical testing	One of the most common TGM1 pathogenic variants causing lamellar ichthyosis, and accounts for approximately one third of all disease-associated alleles among individuals with TGM1-related ichthyosis worldwide (Herman et al., 2009); Canonical splice site variant shown to lead to abnormal splicing and almost complete elimination of transglutaminase 1 enzyme function (Huber et al., 1997; Herman et al., 2009) in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9544844, 10694685, 11298529, 9359043, 16968736, 7824952, 9887377, 10914678, 27025581, 9261103, 29444371, 22437313, 19241467, 28403434, 31168818, 15665393, 31642606, 31980526, 31589614)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000290112	SCV000609885	pathogenic	not provided	2017-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762929	SCV000893349	pathogenic	Autosomal recessive congenital ichthyosis 1	2022-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000290112	SCV000942019	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the TGM1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs142634031, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with congenital ichthyosis (PMID: 7824952, 10914678, 19241467, 27025581, 28403434). ClinVar contains an entry for this variant (Variation ID: 279911). Studies have shown that disruption of this splice site results in inclusion of intron 5 or an insertion of a single nucleotide between exons 5 and 6 and introduces a premature termination codon (PMID: 7824952, 10914678). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000762929	SCV001193896	pathogenic	Autosomal recessive congenital ichthyosis 1	2021-11-18	criteria provided, single submitter	clinical testing	NM_000359.2(TGM1):c.877-2A>G is a canonical splice variant classified as pathogenic in the context of TGM1-related autosomal recessive congenital ichthyosis. c.877-2A>G has been observed in cases with relevant disease (PMID: 9545389, 9887377, 19241467). Functional assessments of this variant are available in the literature (PMID: 9887377). c.877-2A>G has been observed in population frequency databases (gnomAD: NFE 0.06%). In summary, NM_000359.2(TGM1):c.877-2A>G is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genome-Nilou Lab	RCV000762929	SCV002763795	pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000762929	SCV003828040	pathogenic	Autosomal recessive congenital ichthyosis 1	2022-06-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000762929	SCV003921775	pathogenic	Autosomal recessive congenital ichthyosis 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive congenital ichthyosis 1 (MIM#242300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Functional studies showed this variant resulted in abnormal splicing and predicted to result in premature protein termination (PMID: 10914678). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (85 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in individuals with ichthyosis (ClinVar, PMID: 7824952, PMID: 10914678, PMID: 16968736). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.790C>T) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000762929	SCV004203733	pathogenic	Autosomal recessive congenital ichthyosis 1	2024-03-30	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000290112	SCV005198782	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767207	SCV005380832	pathogenic	Lamellar ichthyosis	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: TGM1 c.877-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TGM1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. The variant allele was found at a frequency of 0.00031 in 248880 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (0.00031 vs 0.0021), allowing no conclusion about variant significance. c.877-2A>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Lamellar Ichthyosis (e.g., Pigg_2016). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 27025581). ClinVar contains an entry for this variant (Variation ID: 279911). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000762929	SCV000033544	pathogenic	Autosomal recessive congenital ichthyosis 1	2009-02-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000762929	SCV001459984	pathogenic	Autosomal recessive congenital ichthyosis 1	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000290112	SCV001740716	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000290112	SCV001926555	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000290112	SCV001957213	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000290112	SCV001972344	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001729500	SCV001980667	not provided	Autosomal recessive congenital ichthyosis		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003930035	SCV004746258	pathogenic	TGM1-related disorder	2023-11-29	no assertion criteria provided	clinical testing	The TGM1 c.877-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive congenital ichthyosis (see for example, Sitek et al. 2018. PubMed ID: 29444371; Table 2a, Seidl-Philipp et al. 2020. PubMed ID: 31642606; Pigg et al. 2016. PubMed ID: 27025581; Simpson et al. 2020. PubMed ID: 31168818). This variant is reported in 0.057% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has been reported as a founder variant in Norway (Pigg et al. 2016. PubMed ID: 27025581). Variants that disrupt the consensus splice acceptor site in TGM1 are expected to be pathogenic. This variant is interpreted as pathogenic.