ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.934G>A (p.Gly312Ser) (rs760079636)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246328 SCV000318188 likely pathogenic Cardiovascular phenotype 2018-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,Structural Evidence,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Blueprint Genetics RCV000208245 SCV000264244 likely pathogenic Loeys-Dietz syndrome 2015-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000199247 SCV000250886 likely pathogenic not provided 2016-11-23 criteria provided, single submitter clinical testing The G312S likely pathogenic variant has been published in association with TAAD in at least three unrelated individuals (Singh et al., 2006; Tran-Fadulu et al., 2009; Luo et al., 2016). Singh et al. (2006) initially reported G312S in an individual with a dilated ascending aorta as well as skeletal system involvement, recurrent hernia, and a family history of TAAD. Tran-Fadulu et al. (2009) reported a family with vascular disease in which G312S segregated with ascending aortic aneurysm in one other affected family member, and Luo et al. (2016) described a proband with arterial and aortic root aneurysm/dissection. Furthermore, G312S has been reported to segregate with disease (>10 meioses) in a large family with Loeys-Dietz syndrome (Teixidó-Tura et al., 2016). Moreover, the G312S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The G312S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, there is no published functional data for this variant, and G312S is classified in ClinVar as a variant of uncertain significance and a likely pathogenic variant by two external clinical laboratories (SCV000318188.1; SCV000264244.1; Landrum et al., 2016).Therefore, this variant is likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000208245 SCV000918303 pathogenic Loeys-Dietz syndrome 2018-04-16 criteria provided, single submitter clinical testing Variant summary: TGFBR1 c.934G>A (p.Gly312Ser) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245820 control chromosomes. c.934G>A has been reported in the literature in multiple individuals affected with Aortopathy, including patients and families with Loeys-Dietz Syndrome and TAAD, with strong segregation data (Luo_2016, Singh_2006, Teixido-Tura_2016, Tran-Fadulu_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 likely pathogenic. Additionally, the Montalcino Aortic Consortium reports the variant in 14 patients from an international registry, and showed the variant to have significantly poorer survival without aortic event (dissection or surgery) compared to patients with any other TGFRB1 mutations (Jondeau_2016). Based on the evidence outlined above, the variant was classified as pathogenic.

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