Submissions for variant NM_003239.5(TGFB3):c.164G>A (p.Ser55Asn)

gnomAD frequency: 0.00100  dbSNP: rs143229915

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525678	SCV000561267	likely benign	Rienhoff syndrome	2025-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001696857	SCV000589958	likely benign	not provided	2022-10-14	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000770648	SCV000736233	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-06-14	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	RCV000770648	SCV000902103	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-10-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000497619	SCV000920305	benign	not specified	2018-09-11	criteria provided, single submitter	clinical testing	Variant summary: TGFB3 c.164G>A (p.Ser55Asn) results in a conservative amino acid change located in the TGF-beta, propeptide domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 277224 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0042 in the gnomAD database. This frequency within African control individuals is approximately 168-fold above the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.164G>A has been reported in the literature in an individual affected with aortic root dilation, both parents carried the variant and were unaffected, supporting a benign role (Herrick_2017). Co-occurrence with a pathogenic variant has been observed by our lab (TTR c.424G>A, p.V142I), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852703	SCV000995417	likely benign	Cardiomyopathy	2018-11-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001696857	SCV001471882	likely benign	not provided	2020-03-18	criteria provided, single submitter	clinical testing