ClinVar Miner

Submissions for variant NM_000432.4(MYL2):c.353+12C>A (rs186323458)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036396 SCV000060051 likely benign not specified 2012-03-19 criteria provided, single submitter clinical testing 353+12C>A in intron 5 of MYL2: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. It has been identified in 1/3738 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project ( 353+1 2C>A in intron 5 of MYL2 (allele frequency = 1/3738) **
Illumina Clinical Services Laboratory,Illumina RCV001109259 SCV001266577 likely benign Familial hypertrophic cardiomyopathy 10 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036396 SCV001363621 benign not specified 2019-11-04 criteria provided, single submitter clinical testing Variant summary: MYL2 c.353+12C>A 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. Several computational tools predict a significant impact on normal splicing: Five predict the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 251460 control chromosomes, predominantly at a frequency of 0.0072 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 288 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYL2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.353+12C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

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