Submissions for variant NM_001999.4(FBN2):c.7418G>T (p.Arg2473Leu)

dbSNP: rs28763925

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705108	SCV000250312	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Illumina Laboratory Services, Illumina	RCV000366798	SCV000452548	likely benign	Congenital contractural arachnodactyly	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002315593	SCV000738977	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-03-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000366798	SCV000754901	likely benign	Congenital contractural arachnodactyly	2024-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488451	SCV004241267	likely benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: FBN2 c.7418G>T (p.Arg2473Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251156 control chromosomes. The observed variant frequency is approximately 340-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. c.7418G>T has been reported as a likely benign change in individuals affected with Marfan and Marfan-like syndromes (Wooderchak-Donahue_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25944730). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003907722	SCV004719460	likely benign	FBN2-related disorder	2022-03-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).