Submissions for variant NM_000138.5(FBN1):c.6331T>C (p.Cys2111Arg)

dbSNP: rs363815

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170533	SCV001333117	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-06-28	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374840	SCV001439524	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000663864	SCV005398653	pathogenic	Marfan syndrome	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated TB Family (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Cys2111Tyr) has been reported in ClinVar twice as likely pathogenic and once as pathogenic by clinical laboratories. This variant has also been observed in an individual with Marfan syndrome (MFS) (PMID: 9338581) p.(Cys2111Gly) has been reported once as pathogenic in ClinVar, and has been observed in individuals with MFS (PMIDs: 37042257, 31279624). p.(Cys2111Phe) has been classified as likely pathogenic in an individual with MFS (PMID: 37558401). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in unrelated individuals with suspected Marfan syndrome, and once in an individual with ectopia lentis (PMIDs: 34628919, 37688493, 11826022, 33824467, 37558401, 38190127). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been observed in two affected sons and their affected mother, with the unaffected father not having the variant (PMID: 34628919). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV005253031	SCV005906379	likely pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	Affects a cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within TGF-binding protein domains have been reported in association with FBN1-related disorders (PMIDs: 8281141, 21175431, 7622614; HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 11826022, 38190127, 8281141, 21175431, 7622614, 37688493, 22005308, 33824467, 34628919, 37558401)
Center for Medical Genetics Ghent, University of Ghent	RCV000663864	SCV000787223	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Department of Laboratory Medicine and Genetics, Samsung Medical Center	RCV000663864	SCV005684899	pathogenic	Marfan syndrome	2025-01-02	no assertion criteria provided	clinical testing	The NM_000138.5:c.6331T>C is considered to be rare in the general population database (gnomAD v2.1.1). This variant is predicted to be deleterious by in-silico analysis (REVEL). This variant is located in functional domains and a different missense variant at the same residue is determined to be pathogenic (c.6332G>T, p.Cys2111Phe and c.6332G>A, p.Cys2111Tyr). This variant was found in a patient with suspected or confirmed Marfan syndrome (PMID: 11826022; 33824467; 34456093; 34628919; 38190127). This variant was found in a patient with Marfan syndrome meeting revised Ghent criteria (aortic root dilatation and a systemic score of 9 points) (Samsung Medical Center internal data). According to the ClinGen guidance for PP1/BS4 and PP4 criteria (PMID: 38103548), PP4 with weighted strength was applied. In summary, this variant was classified as a pathogenic variant for Marfan syndrome (PS4, PM1, PM5, PP2, PP3, PP4 with weighted strength, PM2_P).