ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.81T>C (p.Pro27=) (rs147584015)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036034 SCV000059686 benign not specified 2012-07-06 criteria provided, single submitter clinical testing Pro27Pro in Exon 01 of MYL3: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence and has been identified in 0.3% (13/3738) of Africa n American chromosomes from a broad population by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS; dbSNP rs147584015).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000036034 SCV000110308 likely benign not specified 2015-08-12 criteria provided, single submitter clinical testing
Invitae RCV000233955 SCV000284305 benign Hypertrophic cardiomyopathy 2017-11-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000241642 SCV000318425 likely benign Cardiovascular phenotype 2015-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Synonymous alterations with insufficient evidence to classify as benign,Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770183 SCV000901611 benign Cardiomyopathy 2016-10-12 criteria provided, single submitter clinical testing
Color RCV000770183 SCV000913787 benign Cardiomyopathy 2018-10-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000036034 SCV000919838 benign not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: MYL3 c.81T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00045 in 276222 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0048 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 190 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYL3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.81T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all these laboratories classified the variant as benign (1x) / likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.

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