Submissions for variant NM_000138.5(FBN1):c.1285C>T (p.Arg429Ter)

dbSNP: rs112645512

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310720	SCV000319232	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-06-21	criteria provided, single submitter	clinical testing	The p.R429* pathogenic mutation (also known as c.1285C>T), located in coding exon 10 of the FBN1 gene, results from a C to T substitution at nucleotide position 1285. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been reported in several unrelated individuals with classical Marfan syndrome and in one study had confirmed segregation with disease (Matyas G et al. Hum Mutat. 2002;19(4):443-456; Rommel K et al. Hum Mutat. 2002;20(5):406-407; Baudhuin LM et al. J. Hum. Genet., 2015 May;60:241-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000312925	SCV000329345	pathogenic	not provided	2021-09-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 180351; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19293843, 31098894, 27611364, 19618372, 25101912, 12402346, 18435798, 25525159, 11933199, 16835936)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791401	SCV000544841	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180351). This premature translational stop signal has been observed in individuals with Marfan syndrome or suspected Marfan syndrome (PMID: 12402346, 16835936, 18435798, 19618372, 27234404). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg429*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000157224	SCV000781329	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000157224	SCV002025433	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
Fulgent Genetics, Fulgent Genetics	RCV002498777	SCV002798342	likely pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586576	SCV005075869	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1285C>T (p.Arg429X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251556 control chromosomes. c.1285C>T has been reported in the literature in individuals affected with Marfan Syndrome (example, Matyas_2002, Rommel_2002, Collod-Beroud_2003, Rommel_2005, Sakai_2006, Attanasio_ 2008, Magyar_2009, Stheneur_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. The following publications have been ascertained in the context of this evaluation (PMID: 11933199, 12402346, 12938084, 16220557, 16835936, 18435798, 19293843, 19618372). ClinVar contains an entry for this variant (Variation ID: 180351). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000157224	SCV005086449	pathogenic	Marfan syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have rarely been reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic/likely pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783755	SCV005397318	pathogenic	Progeroid and marfanoid aspect-lipodystrophy syndrome	2023-04-25	criteria provided, single submitter	clinical testing	This sequence variant is a single base substitution (C>T) at coding nucleotide 1285 of the FBN1 gene that replaces the Arg429 codon with a premature termition sigl. As it occurs in exon 11 of 66, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or a loss of FBN1 expression due to nonsense-mediated decay. This is a previously reported variant (ClinVar) which has been observed in multiple individuals with Marfan syndrome (PMID: 12402346, 18435798, 19618372, 25101912, 27234404). This variant is absent from the gnomAD population database (0/~282000 alleles). Based on the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP4, PS4, PVS1
Blueprint Genetics	RCV000157224	SCV000206948	pathogenic	Marfan syndrome	2014-05-09	no assertion criteria provided	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000157224	SCV000786741	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Heart Medical Centre, First Affiliated Hospital of Gannan Medical University	RCV000157224	SCV003926545	pathogenic	Marfan syndrome	2021-12-28	no assertion criteria provided	clinical testing