Submissions for variant NM_003193.5(TBCE):c.100+1G>A

gnomAD frequency: 0.00009  dbSNP: rs200356271

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778226	SCV000914394	uncertain significance	Hypoparathyroidism-retardation-dysmorphism syndrome	2017-08-23	criteria provided, single submitter	clinical testing	The TBCE c.100+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for hypoparathyroidism-retardation-dysmorphism syndrome.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198592	SCV001369582	likely pathogenic	Autosomal recessive Kenny-Caffey syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Invitae	RCV001322455	SCV001513329	likely pathogenic	not provided	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the TBCE 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 TBCE are known to be pathogenic (PMID: 27666369, 34134906, 34356170). This variant is present in population databases (rs200356271, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with TBCE-related conditions (PMID: 35432193). ClinVar contains an entry for this variant (Variation ID: 631595). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282366	SCV002572412	likely pathogenic	TBCE-Related Disorders	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: TBCE c.100+1G>A 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. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site, while three predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 249900 control chromosomes (gnomAD). This frequency allows no conclusions about variant significance. The variant, c.100+1G>A, has been reported in the literature in a homozygous individual affected with TBCE-Related Disorder (Globa_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (VUS (n=2), likely pathogenic (n=2)). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001322455	SCV004035564	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35432193)
CeGaT Center for Human Genetics Tuebingen	RCV001322455	SCV004126129	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TBCE: PVS1, PM2
Human Developmental Genetics, Institut Pasteur	RCV001568319	SCV001787110	likely pathogenic	Disorder of sexual differentiation	2021-08-17	no assertion criteria provided	research
Department of Developmental Neurology, Medical University of Gdańsk	RCV001198592	SCV004100908	not provided	Autosomal recessive Kenny-Caffey syndrome		no assertion provided	phenotyping only