ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.732+1G>A (rs730880850)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171825 SCV000054831 pathogenic Cardiomyopathy, left ventricular noncompaction 2013-06-24 criteria provided, single submitter research
GeneDx RCV000158758 SCV000208693 likely pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing The c.732+1 G>A variant in the MYH7 gene has been reported multiple times in association with left ventricular non-compaction (LVNC) (Klaassen et al., 2008; Probst et al., 2011; Hoedemaekers et al., 2013; Ng et al., 2013). Klaassen et al. first reported this variant to segregate with LVNC in seven members from two unrelated families. Hoedemaekers et al. subsequently reported this variant was identified through prenatal ultrasound in a fetus with biventricular cardiomegaly, decreased contractility, increased apical myocardial wall thickness and noncompaction which became evident at 36 weeks gestation. This variant was later identified in the affected father and paternal grandmother as well as in an asymptomatic brother. This variant destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. One additional splice site variant, which impacts the same splice donor site (c.732+3 G>C), has been reported in HGMD in association with LVNC (Stenson et al., 2014). Furthermore, the c.732+1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the majority of pathogenic variants in the MYH7 gene are missense changes, indicating that haploinsufficiency may not be sufficient to cause disease.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Laboratory for Molecular Medicine,Partners HealthCare 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 2016-08-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MYH7 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This truncating variant has been reported to segregate with left ventricular non-compaction in at least three affected families (PMID: 18506004, 22859017). ClinVar contains an entry for this variant (Variation ID: 181320). Experimental studies have shown that this variant results in the loss and generation of aberrant MYH7 mRNA (PMID: 18506004). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015188 SCV000035445 pathogenic Left ventricular noncompaction 5 2008-06-03 no assertion criteria provided literature only

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