Submissions for variant NM_000138.5(FBN1):c.7964C>T (p.Ala2655Val)

gnomAD frequency: 0.00005  dbSNP: rs202240409

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724342	SCV000231913	uncertain significance	not provided	2014-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000724342	SCV000718147	likely benign	not provided	2020-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179634	SCV001337957	likely benign	not specified	2020-01-19	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7964C>T (p.Ala2655Val) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 253322 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.7964C>T has been reported in the literature in sequencing studies of Finnish patients with HCM (Jaaskelainen_2019) and in individuals who did not fulfill the revised Ghent 2010 nosology for Marfan syndrome (Baudhuin_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001180301	SCV001345196	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-11-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001475865	SCV001680063	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-11-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724342	SCV004129794	benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	FBN1: PP2, BP4, BS1, BS2
All of Us Research Program, National Institutes of Health	RCV003996583	SCV004844934	likely benign	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001180301	SCV005113143	benign	Familial thoracic aortic aneurysm and aortic dissection	2024-06-12	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.
PreventionGenetics, part of Exact Sciences	RCV004737285	SCV005362660	likely benign	FBN1-related disorder	2024-09-04	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).