Submissions for variant NM_004281.4(BAG3):c.463G>A (p.Ala155Thr)

gnomAD frequency: 0.00239  dbSNP: rs61756328

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000037894	SCV000051365	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037894	SCV000061556	likely benign	not specified	2017-01-23	criteria provided, single submitter	clinical testing	p.Ala155Thr in exon 2 of BAG3: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, wallaby, opossum, and platypus have a threonine (Thr) at this position despi te high nearby amino acid conservation. Computational analyses (AlignGVGD, PolyP hen2, SIFT) do not suggest a high likelihood of impact to the protein. In additi on, it has been identified in 0.5% (294/63478) of European (Non-Finnish) chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.orgdb SNP; rs61756328).
GeneDx	RCV000037894	SCV000235736	benign	not specified	2017-11-10	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.
Invitae	RCV001080256	SCV000261251	benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037894	SCV000310057	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000247095	SCV000318572	benign	Cardiovascular phenotype	2017-12-01	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga)	RCV000037894	SCV000333198	likely benign	not specified	2015-07-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315530	SCV000360564	uncertain significance	Dilated cardiomyopathy 1HH	2018-01-12	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	RCV000353959	SCV000360565	benign	Myofibrillar myopathy 6	2018-01-12	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590411	SCV000698279	benign	not provided	2017-08-16	criteria provided, single submitter	clinical testing	Variant summary: The BAG3 c.463G>A (p.Ala155Thr) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict benign outcome for this variant. This variant was found in 352/117428 control chromosomes (4 homozygotes) from ExAC and literature at a frequency of 0.0029976, which is approximately 77 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases in ClinVar classified this variant as benign/likely benign. It is also regarded as benign in the literature (Ng_2013). To our knowledge, this variant t has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000037894	SCV000740454	likely benign	not specified	2017-01-27	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852641	SCV000995346	benign	Hypertrophic cardiomyopathy	2018-06-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590411	SCV002821551	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BAG3: BP4, BS1, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486565	SCV004239691	benign	Cardiomyopathy	2023-06-06	criteria provided, single submitter	clinical testing