ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1771A>G (p.Ile591Val) (rs377650301)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000755453 SCV000533101 uncertain significance not provided 2016-10-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The I591V variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium (ExAC). Nevertheless, the I591V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755453 SCV000602390 uncertain significance not provided 2017-05-18 criteria provided, single submitter clinical testing The p.Ile591Val variant (rs377650301) has been previously identified in a single patient in a hypertrophic cardiomyopathy cohort but was categorized as a class 3 variant - unknown pathogenicity (Walsh 2017). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.01 percent (identified on 1 out of 13,006 chromosomes) and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.001 percent (identified on 1 out of 121,390 chromosomes). The p.Ile591Val variant has been reported to ClinVar (Variation ID: 390309) The isoleucine at position 591 is highly conserved, up to Fruitfly (considering 12 species) and computational analyses of the effects of the p.Ile591Val variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ile591Val variant with certainty.

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