Submissions for variant NM_000138.5(FBN1):c.75G>A (p.Ala25=)

gnomAD frequency: 0.00001  dbSNP: rs543230518

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000282784	SCV000332642	benign	not specified	2015-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001705408	SCV000522965	likely benign	not provided	2019-12-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556534	SCV000627992	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-09-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776294	SCV000911588	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000282784	SCV001363507	benign	not specified	2019-06-10	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.75G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00056 in 251464 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 41-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.75G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705408	SCV002049114	benign	not provided	2021-10-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000776294	SCV002673726	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-10-08	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776294	SCV004240593	benign	Familial thoracic aortic aneurysm and aortic dissection	2022-12-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995756	SCV004823161	benign	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing