Submissions for variant NM_000257.4(MYH7):c.5378T>C (p.Leu1793Pro)

dbSNP: rs121913654

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158696	SCV000208631	likely pathogenic	not provided	2021-02-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19138847, 28125727, 19336582, 28973424, 16684601)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001207190	SCV001378532	pathogenic	Hypertrophic cardiomyopathy	2019-09-30	criteria provided, single submitter	clinical testing	This variant has been reported to have conflicting or insufficient data to determine the effect on MYH7 protein function (PMID: 28125727, 19336582, 28973424). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu1793 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 24664454), which suggests that this may be a clinically significant amino acid residue. This variant has been observed in individuals affected with MYH7-related conditions (PMID: 16684601, 19138847, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14123). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1793 of the MYH7 protein (p.Leu1793Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.
Revvity Omics, Revvity	RCV000158696	SCV002017672	pathogenic	not provided	2021-01-27	criteria provided, single submitter	clinical testing
OMIM	RCV003320035	SCV000035438	pathogenic	Myosin storage myopathy	2009-04-14	no assertion criteria provided	literature only
OMIM	RCV000015182	SCV000035439	pathogenic	Hypertrophic cardiomyopathy 1	2009-04-14	no assertion criteria provided	literature only
OMIM	RCV000015183	SCV000035440	pathogenic	Left ventricular noncompaction 5	2009-04-14	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158696	SCV000280365	likely pathogenic	not provided	2014-10-08	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Leu1793Pro (L1793P; c.5378 T>C) in the MYH7 gene, exon 37 Based on the data reviewed below, we consider this variant to be likely disease causing. As such it is suitable for predictive testing of family members. This variant is present in HGMD. It has been reported previously in 2 unrelated families. One of these was the original family reported to have myosin storage myopathy (MSM) by Cancilla et al. in 1971. A brother and sister in this family (ages 2 and 5 at initial publication) were both diagnosed with MSM, with skeletal muscle weakness from birth. The sister sat at 10 months and walked at 18-20 months. She later developed joint contractures of her limbs and severe scoliosis, and required ventilator assistance. She died of bronchopneumonia at age 25. Her younger brother crawled at 15 months, stood with support at 16 months, and walked without support at 20 months. He later developed scoliosis and had a tracheotomy at age 30. The ethnicity of the family is not stated. Dye et al. (2006) performed genetic testing on paraffin-embedded tissue taken from the sister at autopsy. No confirmatory testing was done in the brother. The parents appeared to be unaffected, but no genetic testing was performed for them. Uro-Coste et al. (2009) found this variant in a mother with myosin storage myopathy who developed proximal muscle weakness at age 30 (difficulty climbing stairs or raising her arms above her head). She also had weakness in her ankle dorsiflexors. By age 48 she was in a wheelchair, and her neck flexors and Achilles tendons were retracted. She later at age 51 developed hypertrophic cardiomyopathy. At age 53, exertional dyspnea led to oxygen therapy. Muscle biopsy showed high fiber size variation and increased interstitial fat and connective tissue. Type 2 fibers were hypotrophic and type 1 slow fibers were predominant. There was also fiber splitting and increased internal nuclei. The most prominent change was subsarcolemmal accumulation of hyaline material in type 1 fibers. Positive immunostaining was observed with antibodies to ventricular myosin. At age 58 she had volume-cycled nasal ventilatory support for 15 hours per day. The variant was also present in her daughter who presented at 3 months of age with heart failure due to left ventricular noncompaction. At age 10 the daughter did not complain of muscle weakness, but clinical examination revealed bilateral wasting of the distal leg anterior compartment, and she had some difficulty with heel-walking. The ethnicity of the family is not stated. The authors note that titin and other proteins interact with the myosin tail and could modulate phenotype. Residue 1793 is in the C-terminal extremity of the myosin heavy chain tail domain, or the “light meromyosin region”, which is where other variants shown to cause MSM are located (Dye et al. 2006, Uro-Coste et al. 2009, Armel & Leinwand 2009). This is a conservative amino acid change from a nonpolar leucine to a nonpolar proline in the light meromyosin (LMM) region of the myosin heavy chain tail. The leucine at codon 1793 is highly conserved (100% across 9 vertebrate species). In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Missense variants at nearby residues have also been listed in HGMD: Asp1792Gly, Gln1794Glu, and Glu1801Gly in association with dilated cardiomyopathy (HGMD professional version as of January 17, 2014). This potentially supports the functional importance of this region of the protein. By functional in vitro analysis, Armel and Leinwand (2009) showed that the L1793P mutation does not alter the secondary structure of the protein or the ability to form alpha-helical coiled coils compared to wildtype, but does decrease thermodynamic stability compared to wildtype. The L1793P mutation decreases the ability of LMM to assemble into an LMM rod (akin to forming thick filaments), presumably because of the increased instability of the molecule: Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly into filaments In total the variant has not been seen in ~6500 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes. Dye et al (2006) did not find it in 77 controls. This variant is listed in OMIM and based on this OMIM entry it was added to dbSNP as rs121913654 (as of March 26, 2014).