ClinVar Miner

Submissions for variant NM_000192.3(TBX5):c.787G>A (p.Val263Met) (rs147405081)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620833 SCV000735178 benign Cardiovascular phenotype 2015-10-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000515032 SCV000610894 likely benign not provided 2017-04-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000180104 SCV000232478 likely benign not specified 2018-05-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000299054 SCV000376502 likely benign Holt-Oram syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000180104 SCV000920301 benign not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The TBX5 c.787G>A (p.Val263Met) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Though a recent functional study demonstrated that the variant of interest could disrupts the TBX5-NuRD interaction (Waldron 2016), another study provided evidence that TBX5 activity may be extensively regulated through alternative splicing where the variant of interest would not affect isoforms lacking exon 9 (Yamak 2015). This variant was found in 403/276910 control chromosomes (with 1 homozygous occurrence), predominantly observed in the African subpopulation at a frequency of 0.012288 (295/24008). This frequency is about 2809 times the estimated maximal expected allele frequency of a pathogenic TBX5 variant (0.0000044), strong evidence that this is a benign polymorphism. The variant was reported in the literature in affected individuals, however without strong evidence for causality (Faria 2008, Bonachea 2014), i.e. no clear co-segregation could be demonstrated. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Invitae RCV000233202 SCV000283867 benign Aortic valve disease 2 2017-04-11 criteria provided, single submitter clinical testing

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