ClinVar Miner

Submissions for variant NM_003238.6(TGFB2):c.643+7A>C

gnomAD frequency: 0.01418  dbSNP: rs7531245
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000128393 SCV000171991 benign not specified 2014-05-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001000364 SCV000287903 benign Loeys-Dietz syndrome 4 2024-01-31 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000128393 SCV000309502 benign not specified criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769559 SCV000900956 benign Familial thoracic aortic aneurysm and aortic dissection 2016-07-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000364 SCV001157110 benign Loeys-Dietz syndrome 4 2023-10-16 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001000364 SCV001258131 benign Loeys-Dietz syndrome 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000128393 SCV001362851 benign not specified 2019-08-19 criteria provided, single submitter clinical testing Variant summary: TGFB2 c.643+7A>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 251076 control chromosomes in the gnomAD database, including 20 homozygotes. The observed variant frequency is approximately 270 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Aortopathy phenotype (1.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.643+7A>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported at our laboratory (FBN1 c.349C>T, p.Q117*), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002277277 SCV002566125 likely benign Ehlers-Danlos syndrome 2022-06-08 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV001572650 SCV005280625 benign not provided criteria provided, single submitter not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001572650 SCV001797350 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000128393 SCV001806978 benign not specified no assertion criteria provided clinical testing

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