Submissions for variant NM_004281.4(BAG3):c.181-15C>T

gnomAD frequency: 0.00004  dbSNP: rs397516882

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037888	SCV000061550	uncertain significance	not specified	2012-12-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The 181-15C>T varia nt in BAG3 has not been reported in the literature nor previously identified by our laboratory. This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), though it remains possible that this varia nt is common in other populations. This variant is located in the 3' splice regi on. Computational tools do not suggest an impact to splicing, though this inform ation is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.
Illumina Laboratory Services, Illumina	RCV000280632	SCV000360552	benign	Myofibrillar myopathy 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 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.
Illumina Laboratory Services, Illumina	RCV000337982	SCV000360553	uncertain significance	Dilated cardiomyopathy 1HH	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037888	SCV001338386	benign	not specified	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: BAG3 c.181-15C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.00024 in 250636 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 68-fold the estimated maximal expected allele frequency for a pathogenic variant in BAG3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.181-15C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV002054679	SCV002436732	benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-12	criteria provided, single submitter	clinical testing