ClinVar Miner

Submissions for variant NM_004239.4(TRIP11):c.5719+2T>C (rs199736345)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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 2018-04-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 20) of the TRIP11 gene. While this 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, ExAC 0.01%). This variant has not been reported in the literature in individuals with TRIP11-related disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 Clinical Services Laboratory,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.

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