Submissions for variant NM_004281.4(BAG3):c.1588G>A (p.Val530Met)

gnomAD frequency: 0.00016  dbSNP: rs144678100

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150187	SCV000197108	likely benign	not specified	2013-04-03	criteria provided, single submitter	clinical testing	Val530Met in exon 4 of BAG3: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals, including primates, carry a methionine (Met) at this positio n despite high nearby amino acid conservation. In addition, computational analys es (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelihood of impact to th e protein. The Val530Met variant has also been identified in 4/8600 European Ame rican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs144678100).
Illumina Laboratory Services, Illumina	RCV000329418	SCV000360607	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	RCV000367822	SCV000360608	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.
Invitae	RCV000469156	SCV000550840	uncertain significance	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 530 of the BAG3 protein (p.Val530Met). This variant is present in population databases (rs144678100, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BAG3-related conditions. ClinVar contains an entry for this variant (Variation ID: 162787). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAG3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000618030	SCV000736608	likely benign	Cardiovascular phenotype	2019-10-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582620	SCV001472204	uncertain significance	not provided	2020-02-16	criteria provided, single submitter	clinical testing	The BAG3 c.1588G>A; p.Val530Met variant (rs144678100), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 162787). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the European Non-Finnish population (identified on 41 out of 282,784 chromosomes). The threonine at position 530 is moderately conserved and computational analyses of the effects of the p.Val530Met variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Val530Met variant with certainty.
GeneDx	RCV001582620	SCV001812267	uncertain significance	not provided	2019-11-21	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 162787; Landrum et al., 2016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150187	SCV002570758	likely benign	not specified	2022-07-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001582620	SCV003829755	uncertain significance	not provided	2020-07-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001582620	SCV001926946	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001582620	SCV001974484	likely benign	not provided		no assertion criteria provided	clinical testing