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

gnomAD frequency: 0.00036  dbSNP: rs141259922

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726645	SCV000250912	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Initially identified in a child with LDS and her unaffected father (Loeys et al., 2006); Published in association with Loeys-Dietz syndrome (LDS) and thoracic aortic disease, though not all publications included patient-specific data; also referred to as N401S due to alternate nomenclature (Loeys et al., 2006; Wellbrock et al., 2014; Taylor et al., 2015; Proost et al., 2015; Jondeau et al., 2016; Landis et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21358634, 27879313, 17061023, 27153395, 25985138, 25637381, 25907466, 27647783, 24055113, 34426522, 25116393, 28550590, 16928994)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229867	SCV000288617	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 478 of the TGFBR1 protein (p.Asn478Ser). This variant is present in population databases (rs141259922, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Loeys-Dietz Syndrome (PMID: 16928994, 25116393, 25907466, 25985138). ClinVar contains an entry for this variant (Variation ID: 161393). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TGFBR1 protein function with a negative predictive value of 80%. 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	RCV000229867	SCV000319263	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-13	criteria provided, single submitter	clinical testing	The p.N478S variant (also known as c.1433A>G), located in coding exon 9 of the TGFBR1 gene, results from an A to G substitution at nucleotide position 1433. The asparagine at codon 478 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in Loeys-Dietz syndrome cohorts and thoracic aortic aneurysm and dissection (TAAD) cohorts; however, clinical details were limited in some cases (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Wellbrock J et al. PLoS ONE, 2014 Aug;9:e104742); Proost D et al. Hum. Mutat., 2015 Aug;36:808-14). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Taylor JC et al. Nat. Genet., 2015 Jul;47:717-726: Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000199866	SCV000540517	likely benign	not specified	2018-03-06	criteria provided, single submitter	clinical testing	p.Asn478Ser in exon 9 of TGFBR1: This variant is not expected to have clinical significance because it has been identified in 0.05% (59/125980) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141259922) and in 2 unaffected parents (Loeys 2006). ACMG/AMP Criteria applied: BS2; BS1_Supporting.
Eurofins Ntd Llc (ga)	RCV000726645	SCV000701927	uncertain significance	not provided	2016-10-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726645	SCV000892901	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TGFBR1: PM1, BS1
Color Diagnostics, LLC DBA Color Health	RCV000229867	SCV000913708	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 478 of the TGFBR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 2511639, 25985138), in individuals affected with Marfan-related disorders (PMID: 21358634, 25907466, 28550590) and in individuals affected with thoracic aortic aneurysm (PMID: 25907466, 28550590). This variant has been reported in an unaffected individual and his son showing a phenotype that is not consistent with Loeys-Dietz syndrome (Alsubaie 2018). This variant occurs at an appreciable frequency in the general population and has been identified in 77/281886 chromosomes (61/128464 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000229867	SCV002043332	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277294	SCV002566133	uncertain significance	Ehlers-Danlos syndrome	2020-07-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478418	SCV002789419	uncertain significance	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2022-01-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000148890	SCV003819480	uncertain significance	Loeys-Dietz syndrome 1	2022-01-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726645	SCV004562194	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	The TGFBR1 c.1433A>G; p.Asn478Ser variant (rs141259922), also known as N401S, is reported in individuals with Loeys-Dietz syndrome or thoracic aortic aneurysm and dissection (Loeys 2006, Proost 2015, Wellbrock 2014). In one individual with Loeys-Dietz syndrome, the variant was also detected in their unaffected father (Loeys 2006). The p.Asn478Ser variant is reported in ClinVar (Variation ID: 161393). It is observed in the general population with an overall allele frequency of 0.027% (77/281886 alleles) in the Genome Aggregation Database (v.2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.656). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Loeys BL et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. PMID: 16928994. Proost D et al. Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. Hum Mutat. 2015 Aug;36(8):808-14. PMID: 25907466. Wellbrock J et al. Overexpression of Gremlin-1 in patients with Loeys-Dietz syndrome: implications on pathophysiology and early disease detection. PLoS One. 2014 Aug 12;9(8):e104742. PMID: 25116393.
All of Us Research Program, National Institutes of Health	RCV003998179	SCV004840437	uncertain significance	Loeys-Dietz syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 478 of the TGFBR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 2511639, 25985138), in individuals affected with Marfan-related disorders (PMID: 21358634, 25907466, 28550590) and in individuals affected with thoracic aortic aneurysm (PMID: 25907466, 28550590). This variant has been reported in an unaffected individual and his son showing a phenotype that is not consistent with Loeys-Dietz syndrome (Alsubaie 2018). This variant occurs at an appreciable frequency in the general population and has been identified in 77/281886 chromosomes (61/128464 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000199866	SCV005184958	likely benign	not specified	2024-05-09	criteria provided, single submitter	clinical testing	Variant summary: TGFBR1 c.1433A>G (p.Asn478Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 250492 control chromosomes. The observed variant frequency is approximately 156 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06), strongly suggesting that the variant is benign. c.1433A>G has been reported in the literature in individuals affected with Loeys-Dietz Syndrome and unspecified neurodevelopmental diseases, without strong evidence for causality (Alotibi_2023, Loeys_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36937954, 16928994). ClinVar contains an entry for this variant (Variation ID: 161393). Based on the evidence outlined above, the variant was classified as likely benign.
CSER _CC_NCGL, University of Washington	RCV000148890	SCV000190636	uncertain significance	Loeys-Dietz syndrome 1	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003975170	SCV004789648	uncertain significance	TGFBR1-related disorder	2024-02-20	no assertion criteria provided	clinical testing	The TGFBR1 c.1433A>G variant is predicted to result in the amino acid substitution p.Asn478Ser. This variant was reported in at least two individuals with Loeys-Dietz syndrome, in one of the cases this variant was found also in an unaffected father (Loeys et al. 2006. PubMed ID: 16928994; Wellbrock et al. 2014. PubMed ID: 25116393). This variant was also reported in an individual with thoracic aortic aneurysm (Proost et al. 2015. PubMed ID: 25907466). Furthermore, this variant was reported as a variant of unknown significance by large exome and genome studies, documented as an incidental finding (reported as p.Asn401Ser; Amendola et al. 2015. PubMed ID: 25637381 Table S1; Taylor et al. 2015. PubMed ID: 25985138 Table S10) and by an exome study of families with breast cancer (Maxwell et al. 2016. PubMed ID: 27153395 Table S5). This variant is reported in 0.047% of alleles in individuals of European (Non-Finnish) descent in gnomAD , which is higher than would be expected for causative variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.