ClinVar Genomic variation as it relates to human health

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.

This alteration is classified as 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.

Variant summary: The BAG3 c.772C>T (p.Arg258Trp) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 141/120824 control chromosomes (1 homozygote) from ExAC, predominantly observed in the East Asian subpopulation at a frequency of 0.015647 (135/8628). This frequency is about 401 times the estimated maximal expected allele frequency of a pathogenic BAG3 variant (0.0000391), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been found in one patient with patient with restrictive lung disease, a rapidly progressive proximal myopathy, rigid spine, bilateral Achilles tendon tightening, hypertrophic cardiomyopathy with restrictive physiology and a prolonged QT interval (Lee_2012). The patient also carried a de novo variant c.626C>T (p.Pro209Leu) which is regarded to explain the cardiac disease in the patient. In addition, father who was incidentally found to have prolonged QT interval also carried the variant of interest p.Arg258Trp. Thus the variant of interest may be a functional polymorphism. Multiple clinical diagnostic laboratories in ClinVar classified this variant as benign/likely benign. Taken together, this variant is classified as benign.

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.

p.Arg258Trp in exon 3 of BAG3: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (135/8628) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs117671123).

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.