ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.1433A>G (p.Asn478Ser) (rs141259922)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726645 SCV000250912 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing The N478S variant of uncertain significance in the TGFBR1 gene, also referred to as N401S due to use of alternate nomenclature, has previously been reported in association with LDS (Loeys et al., 2006; Wellbrock et al., 2014; Taylor et al., 2015) and thoracic aortic disease (Proost et al., 2015; Jondeau et al., 2016; Landis et al., 2017). This variant was identified in a child with features of LDS, but was also identified in an unaffected parent (Loeys et al., 2006; Taylor et al., 2015). Landis et al. (2017) identified N478S in a 59 year-old male with severe TAA who had no other features of LDS or other connective tissue disorders. This variant was identified in the patient's two brothers with mild TAA and an unaffected sister (Landis et al., 2017). N478S is observed in 59/125,980 (0.05%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). N478S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000229867 SCV000288617 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 478 of the TGFBR1 protein (p.Asn478Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs141259922, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with Loeys-Dietz Syndrome (PMID: 25116393, 16928994, 25985138) and thoracic aortic aneurysms (PMID: 25907466). This variant is also known in the literature as c.1202A>G: p.N401S. ClinVar contains an entry for this variant (Variation ID: 161393). 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: "Benign"; Align-GVGD: "Class C45"). 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.
Ambry Genetics RCV000617058 SCV000319263 uncertain significance Cardiovascular phenotype 2015-05-11 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting pathogenic classification;Insufficient or conflicting evidence;In silico models in agreement (benign)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000199866 SCV000540517 uncertain significance not specified 2016-04-25 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: VUS in 2/3 papers in HGMD, ExAC: 27/64084 European chromosomes
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726645 SCV000701927 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726645 SCV000892901 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
Color RCV000229867 SCV000913708 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-11-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148890 SCV000190636 uncertain significance Loeys-Dietz syndrome 1 2014-06-01 no assertion criteria provided research

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