Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000475248 | SCV000546226 | pathogenic | Hypertrophic cardiomyopathy | 2018-01-16 | criteria provided, single submitter | clinical testing | A computational algorithm designed to assess the pathogenicity of missense variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). However, this prediction has not been confirmed by published functional studies. For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been observed to be de novo in an individual affected with clinical features of left ventricular noncompaction. In addition, this variant has been reported in the literature to segregate in a family with dilated cardiomyopathy (PMID: 26899768). ClinVar contains an entry for this variant (Variation ID: 407186). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 540 of the MYH7 protein (p.Phe540Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. |
| Rady Children's Institute for Genomic Medicine, |
RCV001267673 | SCV001445908 | likely pathogenic | Cardiomyopathy | 2019-08-05 | criteria provided, single submitter | clinical testing | This variant has been previously reported as a heterozygous change and segregated with disease in a large family with dilated cardiomyopathy (PMID: 26899768). The variant has been classified as Pathogenic by a clinical diagnostic laboratory in the ClinVar database (Variation ID: 407186). The variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1618T>C (p.Phe540Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1618T>C (p.Phe540Leu) variant is classified as Pathogenic. |
| Ambry Genetics | RCV002402248 | SCV002707341 | likely pathogenic | Cardiovascular phenotype | 2016-10-13 | criteria provided, single submitter | clinical testing | The p.F540L variant (also known as c.1618T>C), located in coding exon 14 of the MYH7 gene, results from a T to C substitution at nucleotide position 1618. The phenylalanine at codon 540 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported to segregate with disease in multiple individuals in a family with dilated cardiomyopathy (Cuenca S et al. J Heart Lung Transplant. 2016;35(5):625-35). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Laboratory for Molecular Medicine, |
RCV004017627 | SCV004848564 | likely pathogenic | Primary dilated cardiomyopathy | 2021-05-11 | criteria provided, single submitter | clinical testing | The p.Phe540Leu variant in MYH7 has been reported in 1 individual with dilated cardiomyopathy (DCM) and segregated with disease in 7 affected individuals from one family (Cuenca 2016 PMID: 26899768,). Additionally, it was reported as de novo in one individual with clinical features of left ventricular noncompaction (Invitae data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 407186) and was absent from large population studies. This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with hypertrophic cardiomyopathy (HCM; Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. In addition, computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PP1_Strong, PM2_Supporting, PP3. |