ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.974-2A>C (rs1554701881)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786407 SCV000925225 likely pathogenic not provided 2016-08-17 no assertion criteria provided provider interpretation C.974-2A>C in the TGFBR1 gene Collagen Diagnostic Lab classifies this variant as a likely pathogenic variant. Given the molecular mechanism, combination of clinical findings which match a defect in TGFBR1, we consider this variant likely pathogenic. We recommend further family studies including single site analysis in Ms. Abrena's parents. Per Collagen Diagnostic Lab: "The single basepair substitution disrupts the intron 5 splice acceptor site In mRNA transcripts derived from this allele but the splice outcome is unknown. It could lead to exon 6 skipping or/and use of a cryptic acceptor site upstream in intron 5 or downstream in exon 6. Both exon 6 skip and splicing to the closest available cryptic acceptor sites would lead to a reading frame shift, the introduction of a premature termination codon, and the nonsense-mediated mRNA decay. However, TGFBR1 haploinsufficiency is not known to cause Loeys-Dietz syndrome (LDS). Based on your patient's clinical presentation that appears to be consistent with this diagnosis, we think that use of the cryptic acceptor site 9 nucleotides downstream in exon 6 may be the principle splice outcome. If this were the case, it would result in deletion of 3 amino acid residues [p.(Gly325_Pro327del)] from the highly conserved and functionally important kinase domain of the receptor and be compatible with LDS. Bur mRNA splicing is a complex process and assessment of sequence context only leads to a prediction. To determine the actual outcome, we would need to examine regional mRNA splicing using RNA extracted from cultured dermal fibroblasts. We offer to do the additional splicing study at no charge if we receive cultured cells." This variant is novel. There is no variation at this nuclotide listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 17, 2017).

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