Submissions for variant NM_000257.4(MYH7):c.345+1G>A

dbSNP: rs112907315

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068637	SCV001233760	uncertain significance	Hypertrophic cardiomyopathy	2024-07-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the MYH7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYH7 cause disease. This variant is present in population databases (rs112907315, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with idiopathic ventricular fibrillation and myopathy (PMID: 29343803). ClinVar contains an entry for this variant (Variation ID: 862006). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001179500	SCV001344170	uncertain significance	Cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 4 of the MYH7 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with idiopathic ventricular fibrillation and myopathy (PMID: 29343803). It has also been reported in an individual affected with ischemic cardiomyopathy and cardiac amyloidosis who also carried a pathogenic variant in the TTR gene (PMID: 36923113). This variant has been identified in 4/251260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 splice and 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.
GeneDx	RCV001576686	SCV001803923	uncertain significance	not provided	2019-10-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29343803)
Ambry Genetics	RCV002451299	SCV002617050	uncertain significance	Cardiovascular phenotype	2024-07-25	criteria provided, single submitter	clinical testing	The c.345+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the MYH7 gene. This variant has been identified in an individual with idiopathic ventricular fibrillation and myopathy (Broendberg AK et al. Eur. J. Hum. Genet., 2018 03;26:303-313). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of MYH7 has not been clearly established as a mechanism of disease. Based on the available evidence, the clinical significance of this variant remains unclear.
Baylor Genetics	RCV003147583	SCV003835495	uncertain significance	Dilated cardiomyopathy 1S	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147587	SCV003835508	uncertain significance	Hypertrophic cardiomyopathy 1	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320229	SCV003835528	uncertain significance	Myosin storage myopathy	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147588	SCV003835529	uncertain significance	Myopathy, myosin storage, autosomal recessive	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320229	SCV003835530	uncertain significance	Myosin storage myopathy	2022-09-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147586	SCV003836484	uncertain significance	MYH7-related skeletal myopathy	2022-09-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001179500	SCV004828128	uncertain significance	Cardiomyopathy	2024-05-17	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 4 of the MYH7 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with idiopathic ventricular fibrillation and myopathy (PMID: 29343803). It has also been reported in an individual affected with ischemic cardiomyopathy and cardiac amyloidosis who also carried a pathogenic variant in the TTR gene (PMID: 36923113). This variant has been identified in 4/251260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYH7 splice and 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256695	SCV001433096	likely pathogenic	Conduction disorder of the heart	2019-08-20	flagged submission	clinical testing