Submissions for variant NM_004239.4(TRIP11):c.5719+2T>C

gnomAD frequency: 0.00014  dbSNP: rs199736345

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824805	SCV000712781	uncertain significance	not specified	2018-12-19	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.5719+2T>C variant in TRIP11 has not been reported in individuals with Achondrogenesis typ e 1A but has been identified in 0.016% (20/127174) of European chromosomes by gn omAD (http://gnomad.broadinstitute.org). This variant occurs within the canonica l splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein; however, this splice variant disrupts the donor spl ice site of the penultimate exon and therefore may escape nonsense mediated deca y. Additionally, no loss of function variants downstream of this variant have be en reported in individuals with disease. In summary, while there is some suspici on for a pathogenic role, the clinical significance of the c.5719+2T>C variant i s uncertain. ACMG/AMP Criteria applied: PVS1_Moderate.
Invitae	RCV000610429	SCV000835662	uncertain significance	Achondrogenesis, type IA	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 20 of the TRIP11 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs199736345, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TRIP11-related conditions. ClinVar contains an entry for this variant (Variation ID: 505515). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000610429	SCV000914657	uncertain significance	Achondrogenesis, type IA	2018-12-25	criteria provided, single submitter	clinical testing	This 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 this disease.
GeneDx	RCV001764723	SCV002008955	uncertain significance	not provided	2022-02-14	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; Has not been previously reported as pathogenic or benign in association with a TRIPP11-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 30609409)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000824805	SCV004122944	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: TRIP11 c.5719+2T>C 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: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. To our knowledge c.5719+2T>C has not been reported in the literature in individuals affected with TRIP11-Related Disorders and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30609409, 33578785). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001764723	SCV004563882	uncertain significance	not provided	2023-10-02	criteria provided, single submitter	clinical testing