Submissions for variant NM_001613.4(ACTA2):c.390T>C (p.Asn130=)

gnomAD frequency: 0.00003  dbSNP: rs141933412

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094010	SCV000365844	uncertain significance	Aortic aneurysm, familial thoracic 6	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000299200	SCV000365845	likely benign	Multisystemic smooth muscle dysfunction syndrome	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000443506	SCV000511958	benign	not specified	2015-06-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586209	SCV000697867	likely benign	not provided	2016-06-13	criteria provided, single submitter	clinical testing	Variant summary: The ACTA2 c.390T>C (p.Asn130Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict no significant change to normal splicing. This variant was found in 3/99802 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000549 (3/54630). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic ACTA2 variant (0.0000175), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Likely Benign until additional information is available.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680450	SCV000807823	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000403856	SCV000913686	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001094010	SCV001610139	likely benign	Aortic aneurysm, familial thoracic 6	2022-10-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586209	SCV001746025	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000403856	SCV004840655	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-12-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000403856	SCV005017828	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-12-25	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.