Submissions for variant NM_000359.3(TGM1):c.232C>T (p.Arg78Ter)

gnomAD frequency: 0.00002  dbSNP: rs760429286

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519659	SCV000617729	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7581379, 23895935)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192957	SCV001361442	pathogenic	Lamellar ichthyosis	2019-09-25	criteria provided, single submitter	clinical testing	Variant summary: TGM1 c.232C>T (p.Arg78X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 1.2e-05 in 250334 control chromosomes. c.232C>T has been reported in the literature in individuals affected with Lamellar ichthyosis, including two affected brothers from the same family (Parmentier_1995, Sugiura_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000665611	SCV002058903	pathogenic	Autosomal recessive congenital ichthyosis 1	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000449511, PMID:7581379, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000665611	SCV002764128	pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000519659	SCV003288784	pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449511). This premature translational stop signal has been observed in individual(s) with lamellar ichthyosis (PMID: 7581379). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760429286, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg78*) in the TGM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGM1 are known to be pathogenic (PMID: 18948357, 19241467).
Baylor Genetics	RCV000665611	SCV004203771	pathogenic	Autosomal recessive congenital ichthyosis 1	2023-08-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000665611	SCV000789761	pathogenic	Autosomal recessive congenital ichthyosis 1	2017-02-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000665611	SCV001459992	pathogenic	Autosomal recessive congenital ichthyosis 1	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003900087	SCV004712471	pathogenic	TGM1-related disorder	2024-02-27	no assertion criteria provided	clinical testing	The TGM1 c.232C>T variant is predicted to result in premature protein termination (p.Arg78*). This variant has been reported in the homozygous state in several individuals with ichthyosis (Parmentier et al. 1995. PubMed ID: 7581379; Khan et al. 2023. PubMed ID: 36789964); and, it has been observed to co-segregate with disease in the affected family members (same studies). It has also been reported in the compound heterozygous state in a mildly affected patient along with a second TGM1 missense variant of uncertain significance (Sugiura et al. 2013. PubMed ID: 23895935). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in TGM1 are expected to be pathogenic. This variant is interpreted as pathogenic.