Submissions for variant NM_004281.4(BAG3):c.1240G>A (p.Glu414Lys)

gnomAD frequency: 0.00024  dbSNP: rs117749531

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150185	SCV000197105	uncertain significance	not specified	2014-08-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Glu414Lys varia nt in BAG3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 3/8600 European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs117749531). Gl utamic acid (Glu) at position 414 is not conserved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be t olerated. Additional computational prediction tools suggest that this variant ma y not impact the protein, though this information is not predictive enough to ru le out pathogenicity. In summary, while the clinical significance of the Glu414L ys variant is uncertain, these data suggest that it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV000296394	SCV000360595	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.
Illumina Laboratory Services, Illumina	RCV000335067	SCV000360596	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.
Invitae	RCV001081810	SCV000650659	benign	Myofibrillar myopathy 6; Dilated cardiomyopathy 1HH	2024-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000836269	SCV000978110	benign	not provided	2019-07-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25617006)
CeGaT Center for Human Genetics Tuebingen	RCV000836269	SCV001148110	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BAG3: BP4, BS1, BS2
Ambry Genetics	RCV002381463	SCV002671036	likely benign	Cardiovascular phenotype	2022-08-05	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.
Dept of Medical Biology, Uskudar University	RCV003318354	SCV004021962	likely benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, BP1
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000836269	SCV001741978	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000836269	SCV001927891	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000836269	SCV001959973	likely benign	not provided		no assertion criteria provided	clinical testing