Submissions for variant NM_000138.5(FBN1):c.4930C>T (p.Arg1644Ter)

dbSNP: rs140630

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181693	SCV000233996	pathogenic	not provided	2017-01-17	criteria provided, single submitter	clinical testing	The R1644X pathogenic variant in the FBN1 gene has been published multiple times in association with Marfan syndrome (Loeys et al., 2001; Schrijver et al., 2002; Biggin et al., 2004; Arbustini et al., 2005; Rand-Hendriksen et al., 2007; Söylen et al., 2009; Pees et al., 2014). R1644X was reported as a de novo variant in two unrelated patients with Marfan syndrome, although maternity and paternity were not confirmed (Arbustini et al., 2005; Söylen et al., 2009). The R1644X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other downstream nonsense variants in the FBN1 gene have been reported in Human Gene Mutation Database in association with Marfan syndrome or another FBN1-related disorder (Stenson et al., 2014). Furthermore, the R1644X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics	RCV002310748	SCV000319230	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-06-30	criteria provided, single submitter	clinical testing	The p.R1644* pathogenic mutation (also known as c.4930C>T), located in coding exon 39 of the FBN1 gene, results from a C to T substitution at nucleotide position 4930. This changes the amino acid from an arginine to a stop codon within coding exon 39, located in the cbEGF-like #23 domain. This mutation has been reported as de novo in several patients with classic Marfan syndrome (Arbustini E et al. Hum. Mutat., 2005 Nov;26:494; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637). This recurrent mutation has also been reported in familial cases (Rand-Hendriksen S et al. Am J Med Genet A. 2007;143A(17):1968-77; Pees C et al. Clin Genet. 2014;86(6):552-7, Hung CC et al. Ann. Hum. Genet., 2009 Nov;73:559-67), as well as detected in several Marfan syndrome patients in our laboratory (Ambry internal data). In addition to the clinical data, premature stop codons are typically deleterious in nature, as they are expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay, and in fact, quantitative assay for this mutation has shown reduced fibrillin synthesis and reduction of extracellular matrix deposition compared to normal control values (Schrijver I et al. Am J Hum Genet. 2002;71(2):223-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000631940	SCV000753043	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1644*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 14695540, 16222657, 19159394, 24199744). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200186). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181693	SCV000885416	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing	The FBN1 c.4930C>T, p.Arg1644Ter variant (rs140630) has been reported in multiple individuals diagnosed with Marfan syndrome (Biggin 2004, Hung 2009, Loeys 2001, Schrijver 2002), and has been found as a de-novo alteration (Soylen 2009) or segregating with affected individuals in familial cases (Rand-Hendriksen 2007). RNA analysis of patient cells show no detectable transcripts generated from the variant allele, suggesting that the variant mRNA is subjected to nonsense mediated decay (Schrijver 2002). The variant is listed as pathogenic in ClinVar (Variation ID: 200186), and not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, the p.Arg1644Ter variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780237	SCV000917345	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2018-02-26	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4930C>T (p.Arg1644X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 247204 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FBN1 causing Marfan Syndrome (2e-05 vs 0.00011), allowing no conclusion about variant significance. c.4930C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Biggin 2004, Hung 2009, Loeys 2001, Pees 2013, Rand-Hendriksen 2007, Schrijver 2002, Stheneur 2009, Franken 2016) including two de novo cases (Arbustini 2005, Soylen 2009), though paternity were not confirmed. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Schrijver 2002). The most pronounced variant effect results in 10%-<30% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374847	SCV001439531	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Centre of Medical Genetics, University of Antwerp	RCV000663756	SCV002025335	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS1, PP4
Color Diagnostics, LLC DBA Color Health	RCV002310748	SCV004357371	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-07-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 40 of the FBN1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten unrelated individuals affected with Marfan syndrome or related diseases (PMID: 11700157, 12068374, 17663468, 19839986, 24199744, 25652356, 25656438, 29768367, 31098894, 31536524). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of FBN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663756	SCV000787100	pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing