Submissions for variant NM_000359.3(TGM1):c.876+2T>C

gnomAD frequency: 0.00004  dbSNP: rs151054393

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414414	SCV000490848	pathogenic	not provided	2019-01-21	criteria provided, single submitter	clinical testing	The c.876+2 T>C variant in the TGM1 gene has been reported previously in association with autosomal recessive congenital ichthyosis (Farasat et al., 2009). This splice site variant destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, the c.876+2 T>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.876+2 T>C as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000414414	SCV000862778	pathogenic	not provided	2018-08-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000673993	SCV002060226	pathogenic	Autosomal recessive congenital ichthyosis 1	2021-11-16	criteria provided, single submitter	clinical testing	NM_000359.2(TGM1):c.876+2T>C is a canonical splice variant classified as pathogenic in the context of TGM1-related autosomal recessive congenital ichthyosis. c.876+2T>C has been observed in cases with relevant disease (PMID: 28403434, 18948357, 19241467, 22437313). Functional assessments of this variant are not available in the literature. c.876+2T>C has been observed in population frequency databases (gnomAD: NFE 0.005%). In summary, NM_000359.2(TGM1):c.876+2T>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and 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.
Invitae	RCV000414414	SCV002298641	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the TGM1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TGM1 are known to be pathogenic (PMID: 18948357, 19241467). This variant is present in population databases (rs151054393, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with congenital ichthyosis (PMID: 18948357, 22437313, 28403434). This variant is also known as IVS5+2T>C. ClinVar contains an entry for this variant (Variation ID: 372533). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000673993	SCV002763806	likely pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000673993	SCV004203781	pathogenic	Autosomal recessive congenital ichthyosis 1	2023-07-23	criteria provided, single submitter	clinical testing