Submissions for variant NM_000257.4(MYH7):c.732+1G>A

dbSNP: rs730880850

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV001256089	SCV000054831	pathogenic	Left ventricular noncompaction cardiomyopathy	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000158758	SCV000208693	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Reported in probands with Ebstein anomaly, including a fetus with additional features of left ventricular hypertrophy, dilation, and noncompaction (Sicko et al., 2016; Tu et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing; other splice site variants in the MYH7 gene have been reported in association with cardiomyopathy (HGMD); Predicted to cause exon skipping that would disrupt the myosin motor domain; however, in the absence of definitive functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25525159, 29300372, 18506004, 21551322, 12749056, 22859017, 35209905, 27788187, 30847666, 33500567, 34758253, 35877568, 36292635, 23861362)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214568	SCV000271412	pathogenic	Left ventricular noncompaction	2017-01-31	criteria provided, single submitter	clinical testing	c.732+1G>A (MYH7; NM_000257.2; Chr14g.23900793C>T; GRCh37): The c.732+1G>A (also reported as c.818+1G>A) variant in MYH7 has been reported in 3 adults and 1 inf ant with LVNC, segregated with disease in 9 affected relatives from 3 families ( Klaassen 2008, Hoedemaeker 2013, Ng 2013). It has been identified in 1/17348 Eas t Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org/; dbSNP rs397516266). This variant occurs in the invariant regi on (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meet s criteria to be classified as pathogenic for LVNC in an autosomal dominant mann er based upon predicted impact on the protein, presence in multiple affected ind ividuals, significant segregation evidence, and an extremely low frequency in th e general population.
Invitae	RCV000477002	SCV000546272	pathogenic	Hypertrophic cardiomyopathy	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with Ebstein anomaly and left ventricular non-compaction (PMID: 18506004, 22859017, 27788187). It has also been observed to segregate with disease in related individuals. This variant is also known as c.818+1G>A. ClinVar contains an entry for this variant (Variation ID: 14127). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV001256089	SCV001432876	pathogenic	Left ventricular noncompaction cardiomyopathy	2020-01-16	criteria provided, single submitter	clinical testing	The c.732+1G>A variant identified in the MYH7 gene substitutes a completely conserved Guanine for Adenine at the +1 canonical splice site in intron8/39 (+1 splice donor of exon 8). This variant is found with low frequency in gnomAD (1 heterozygote, 0 homozygotes; allele frequency: 3.98e-6), suggesting it is not a common benign variant in the populations represented in this database. This variant is reported as Pathogenic in ClinVar (VarID:14127), and has been identified in several individuals and families in the literature with left ventricular noncompaction and noncompaction cardiomyopathy [PMID: 18506004; PMID: 21551322; PMID: 22859017; PMID: 23861362]. Given its position at a canonical splice donor site, its low frequency in population databases, and presence in affected individuals and families in the literature in which it segregates with disease, the c.732+1G>A variant identified in the MYH7 gene is reported here as Pathogenic.
Ambry Genetics	RCV003298034	SCV003993387	likely pathogenic	Cardiovascular phenotype	2023-04-12	criteria provided, single submitter	clinical testing	The c.732+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the MYH7 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, this alteration has been reported in several individuals with left ventricular non-compaction (LVNC) and segregated with disease in two families (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Hoedemaekers YM et al. Ultrasound Obstet Gynecol, 2013 Mar;41:336-9; Kelly MA et al. Genet Med, 2018 Mar;20:351-359; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000015188	SCV000035445	pathogenic	Left ventricular noncompaction 5	2008-06-03	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542486	SCV001760335	likely pathogenic	Hypertrophic cardiomyopathy 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000158758	SCV001920278	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158758	SCV001957130	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158758	SCV001972097	pathogenic	not provided		no assertion criteria provided	clinical testing