Submissions for variant NM_000432.4(MYL2):c.431_432del (p.Pro144fs)

dbSNP: rs1566147422

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770390	SCV000901831	likely pathogenic	Cardiomyopathy	2020-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770390	SCV001358331	uncertain significance	Cardiomyopathy	2023-04-27	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pediatrics, The University of Tokyo	RCV001507317	SCV001712278	pathogenic	Congenital myopathy with fiber type disproportion	2021-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003166034	SCV003864501	uncertain significance	Cardiovascular phenotype	2023-02-03	criteria provided, single submitter	clinical testing	The c.431_432delCT variant, located in coding exon 7 of the MYL2 gene, results from a deletion of two nucleotides at nucleotide positions 431 to 432, causing a translational frameshift with a predicted alternate stop codon (p.P144Rfs*57). This alteration occurs at the 3' terminus of theMYL2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 13% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported as homozygous in a case report with ventricular hypertrophy and hypotonia, passing away from refractory cardiogenic shock (Manivannan SN et al. PLoS Genet, 2020 May;16:e1008639). Additionally, this alteration was found in trans with an additional alteration in MYL2 in two siblings with muscle weakness and dilated cardiomyopathy (Tamamitsu AM et al. Int Heart J, 2021 Mar;62:445-447). Lastly, this alteration was detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Wang C et al. J Am Heart Assoc, 2017 Aug;6:[ePub ahead of print]; Hirono K et al. Circ Genom Precis Med, 2020 Aug;13:e002940). Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999941	SCV004845819	uncertain significance	Hypertrophic cardiomyopathy	2023-08-28	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 of the MYL2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using patient-derived mRNA showed a slight reduction in active mRNA compared to wild-type controls (PMID: 32453731). This variant has been reported in homozygous state in an individual affected with infantile-onset hypertrophic cardiomyopathy; both heterozygous parents were clinically unaffected (PMID: 32453731). It has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 33731536) and in an individual affected with left ventricular non-compaction (PMID: 28855170). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Garg Lab, Nationwide Children's Hospital	RCV001089865	SCV001245294	pathogenic	Hypertrophic cardiomyopathy 10	2020-03-17	no assertion criteria provided	research	The variant is observed to be pathogenic only if homozygous, at least for the infantile presentation, and not pathogenic (or weakly expressed with no obvious disease) if heterozygous
OMIM	RCV001553794	SCV001774791	pathogenic	Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	2021-08-06	no assertion criteria provided	literature only