Submissions for variant NM_001999.4(FBN2):c.728T>C (p.Ile243Thr)

gnomAD frequency: 0.00674  dbSNP: rs117524265

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513981	SCV000168530	benign	not provided	2021-02-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16835936, 31426022)
Eurofins Ntd Llc (ga)	RCV000179399	SCV000231644	benign	not specified	2015-05-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000179399	SCV000308647	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310705	SCV000317900	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-02-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000404713	SCV000452649	benign	Congenital contractural arachnodactyly	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000404713	SCV000563020	benign	Congenital contractural arachnodactyly	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513981	SCV000603692	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513981	SCV000609849	likely benign	not provided	2017-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000513981	SCV000697903	benign	not provided	2017-03-29	criteria provided, single submitter	clinical testing	Variant summary: The FBN2 c.728T>C (p.Ile243Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within a TB domain (InterPro) and 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.009478 (1150/121334 control chromosomes [18 homozygotes]), which is approximately 7582 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In a study of 49 Marfan syndrome or suspected Marfan syndrome patients where several disease-related genes were sequenced, including FBN2, the variant was detected and described as a polymorphism (Sakai_FBN1_AJMGA_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659594	SCV000781433	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513981	SCV002563855	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FBN2: BS1, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277270	SCV002565962	benign	Ehlers-Danlos syndrome	2021-11-13	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000659594	SCV002566595	benign	Connective tissue disorder	2021-08-04	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000513981	SCV005225326	likely benign	not provided		criteria provided, single submitter	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000513981	SCV001800741	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000179399	SCV001931263	benign	not specified		no assertion criteria provided	clinical testing