Submissions for variant NM_000138.5(FBN1):c.493C>T (p.Arg165Ter)

dbSNP: rs113905529

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035214	SCV000058859	pathogenic	Marfan syndrome	2012-03-22	criteria provided, single submitter	clinical testing	The Arg165X variant has previously been reported in 3 individuals with clinical features of Marfan syndrome (Rybczynski 2008, Rommel 2005, Soylen 2009). In addi tion, this variant has been identified in 3 other unrelated probands tested by o ur laboratory and cosegregates with clinical features in two families. This nons ense variant leads to a premature termination codon at position 165, which is pr edicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) bas ed upon predicted effect on the protein, presence in symptomatic individuals and segregation in symptomatic family members.
GeneDx	RCV000484323	SCV000568643	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19012347, 25525159, 16220557, 25101912, 31279664, 31536524, 29357934, 33824467, 31098894, 19159394)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810295	SCV000950489	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg165*) 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 individuals with Marfan syndrome (PMID: 16220557, 19159394, 25101912). ClinVar contains an entry for this variant (Variation ID: 42373). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170329	SCV001332900	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-10-04	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374823	SCV001439572	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
3billion	RCV000035214	SCV002521437	pathogenic	Marfan syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000042373). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV001170329	SCV002643888	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-10-07	criteria provided, single submitter	clinical testing	The p.R165* pathogenic mutation (also known as c.493C>T), located in coding exon 5 of the FBN1 gene, results from a C to T substitution at nucleotide position 493. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been previously reported in individuals with clinical features of Marfan syndrome (Rommel K et al. Hum Mutat. 2005;26(6):529-39; Rybczynski M et al. Am J Med Genet. 2008;146A(24):3157-66; Söylen B et al. Clin Genet. 2009;75(3):265-70). 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.