Submissions for variant NM_000432.4(MYL2):c.403-1G>C

gnomAD frequency: 0.00004  dbSNP: rs199474813

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000024459	SCV000208867	likely pathogenic	not provided	2021-03-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrated that the c.403-1G>C variant destroys the consensus splice acceptor site of intron 6, and that utilization of an upstream cryptic splice site results in replacement of the last 32 amino acid residues with 20 different amino acid residues and alters the C-terminal domain of MYL2 (Weterman et al., 2013); however additional studies are needed to validate the functional effect of this variant in vivo; Canonical splice site variant with an unclear effect on protein function; Reported in ClinVar as pathogenic (ClinVar Variant ID# 31768; Landrum et al., 2016); Observed in 11 Dutch infant patients, homozygous for c.403-1 G>C, who subsequently died from cardiomyopathy; predicted variants in this region of the MYL2 gene may only lead to disease when present in a homozygous state (Weterman et al., 2013); Observed in a 17 year-old Danish male individual with pronounced septal hypertrophy who inherited this variant from his affected father (Andersen et al., 2001); however, the proband's sister also harbored the variant and had no features of hypertrophy on ECG or echocardiogram (Andersen et al., 2001). Both the proband and his sister also harbored a missense variant in MYL2, located on the opposite MYL2 allele (in trans), and inherited from their unaffacted mother (Andersen et al., 2001).; This variant is associated with the following publications: (PMID: 24474197, 21415409, 23365102, 27378946, 29447731, 11748309, 30291343, 30847666, 31980526, 31620961, 31127036, 32665702)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466598	SCV000549156	pathogenic	Hypertrophic cardiomyopathy 10	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the MYL2 gene. It does not directly change the encoded amino acid sequence of the MYL2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs199474813, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive MYL2-related conditions (PMID: 11748309, 23365102). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant hypertrophic cardiomyopathy (PMID: 11748309); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 31768). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MYL2 function (PMID: 27378946). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site 23 nucleotides upstream of the original splice site and introduces a new termination codon (PMID: 23365102). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000466598	SCV000914563	likely pathogenic	Hypertrophic cardiomyopathy 10	2018-11-07	criteria provided, single submitter	clinical testing	The MYL2 c.403-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.403-1G>C variant has been identified in a homozygous state in 11 probands from eight unrelated families, in a compound heterozygous state in two probands, and in a heterozygous state in one proband (Andersen et al. 2001; Weterman et al. 2013). All the homozygous probands died within six months of birth (Weterman et al. 2013). Parents for seven of the homozygous probands were found to be heterozygous for the c.403-1G>C variant but did not exhibit any clinical phenotype consistent with familial hypertrophic cardiomyopathy. Phenotypes of affected individuals included familial hypertrophic cardiomyopathy, pronounced proximal septal hypertrophy, and light chain myopathy (Andersen et al. 2001; Weterman et al. 2013). The c.403-1G>C variant was absent from 150 control subjects and is reported at a frequency of 0.000083 in the European (non-Finnish) population of the Genome Aggregation Database. Analysis of mRNA from proband muscle tissue identified activation of cryptic splice site that causes a frameshift which leads to the C-terminal region of the protein being altered (Weterman et al. 2013). In vitro analysis of c.403-1G>C in BL21 (DE3) cells found reduced binding to myosin heavy chain, decreased maximal contractile force, and induced conformational changes to the regulatory light chain protein when compared to wildtype (Zhou et al. 2016). Due to the potential impact of splice acceptor variants, the c.403-1G>C variant is classified as pathogenic for MYL2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000466598	SCV001950077	likely pathogenic	Hypertrophic cardiomyopathy 10	2022-05-04	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1_STR, PS4, PS3_SUP, PM2_SUP
AiLife Diagnostics, AiLife Diagnostics	RCV000024459	SCV002501765	likely pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001553791	SCV002580709	pathogenic	Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	2022-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162260	SCV003901320	uncertain significance	Cardiovascular phenotype	2024-05-29	criteria provided, single submitter	clinical testing	The c.403-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 7 of the MYL2 gene. This alteration has been identified in the homozygous state in multiple individuals from the Netherlands with infantile type I muscle fibre disease and cardiomyopathy, and haplotype analysis indicates that this variant is a Dutch founder mutation (Weterman MA et al. Brain, 2013 Jan;136:282-93). This alteration has also been reported in the homozygous state in a child with left ventricular noncompaction and in the heterozygous state in hypertrophic cardiomyopathy cohorts (Andersen PS et al. J. Med. Genet., 2001 Dec;38:E43; van Velzen HG et al. Am. J. Cardiol., 2016 09;118:881-887; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing. RNA studies have demonstrated that an alternate splice acceptor site located 23 nucleotides upstream of the native acceptor site is utilized in the presence of this alteration, resulting in the inclusion of 23 intronic nucleotides and a predicted frameshift (p.V135Hfs*20) that disrupts the C-terminal EF hand domain (Weterman MA et al. Brain, 2013 Jan;136:282-93). In vitro functional assays suggest that the resulting truncated protein alters MYL2 function, but the physiological relevance of this result is unclear (Zhou Z et al. Front Physiol, 2016 Jun;7:240). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Although biallelic loss of function of MYL2 has been associated with autosomal recessive MYL2-related infantile onset myofibrillar myopathy with cardiomyopathy, haploinsufficiency of MYL2 has not been established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive MYL2-related infantile onset myofibrillar myopathy with cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant MYL2-related cardiomyopathy is unclear.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000024459	SCV005199411	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (MYL2)	RCV000024459	SCV000045760	not provided	not provided	2012-03-26	no assertion provided	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000024459	SCV001740281	pathogenic	not provided		no assertion criteria provided	clinical testing
OMIM	RCV001553791	SCV001774788	pathogenic	Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	2021-08-05	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000024459	SCV001925271	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000024459	SCV001927076	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000024459	SCV001953690	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000024459	SCV001969329	pathogenic	not provided		no assertion criteria provided	clinical testing