ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.134A>G (p.Asn45Ser) (rs387906696)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766900 SCV000250868 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing The Asn45Ser variant in the TGFBR1 gene has been reported as a pathogenic variant in one Scottish family with MSSE (Goudie D et al., 2011). Goudie et al. reported Asn45Ser in two symptomatic relatives and in one asymptomatic relative, and it was absent from 80 Scottish control individuals. Other missense variants associated with MSSE also cluster in exon 2 of TGFBR1, including the common Scottish MSSE mutation Gly52Arg. Also, the Asn45Ser substitution 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000654793 SCV000776693 uncertain significance Thoracic aortic aneurysm and aortic dissection 2017-11-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 45 of the TGFBR1 protein (p.Asn45Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs387906696, ExAC 0.006%). This variant has been reported in a family affected with multiple self-healing squamous epithelioma (PMID: 21358634). ClinVar contains an entry for this variant (Variation ID: 29915). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454530 SCV000540520 uncertain significance not specified 2016-12-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in a Scottish family with Multiple self-healing squamous epithelioma (MSSE - 2 affected and 1 unaffected relative). This variant is classified in ClinVar with 1 star as Pathogenic by GeneDx and a risk factor by OMIM. It has a Max MAF of 0.006% in ExAC (1 allele) and 0.003% in gnomAD (1 allele).
OMIM RCV000022802 SCV000044091 risk factor Multiple self healing squamous epithelioma 2011-02-27 no assertion criteria provided literature only

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