Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000786175 | SCV000059457 | uncertain significance | not provided | 2023-05-04 | criteria provided, single submitter | clinical testing | The p.Thr857Ile variant in MYH7 has been reported in 1 individual with HCM who had another pathogenic variant in the same gene that explained their disease (Walsh 2017 PMID: 27532257, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42917) and has also been identified in 0.001% (1/68034) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v. 3.1.2). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2_Supporting, BP4, BP5. |
| Labcorp Genetics |
RCV000546729 | SCV000623674 | uncertain significance | Hypertrophic cardiomyopathy | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 857 of the MYH7 protein (p.Thr857Ile). This variant is present in population databases (rs397516158, gnomAD 0.002%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42917). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. 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 disrupts the p.Thr857 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28986455). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Fulgent Genetics, |
RCV002490486 | SCV002792558 | uncertain significance | Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy | 2021-09-15 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV003531917 | SCV004356914 | uncertain significance | Cardiomyopathy | 2023-07-06 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with isoleucine at codon 857 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). This variant has been identified in 3/282848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786175 | SCV000924881 | uncertain significance | not provided | 2017-11-10 | no assertion criteria provided | provider interpretation | p.Thr857Ile (c.2570C>T) in exon 22 of the MYH7 gene (NM_000257.3; chr14-23894087-G-A) SCICD Classification: variant of uncertain significance based on lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: MYH7: MYH7 encodes the b-cardiac myosin heavy chain. Pathogenic variants in MYH7 are a common cause of hypertrophic cardiomyopathy (HCM). MYH7 is highly constrained for genetic variation. The majority of pathogenic variants in MYH7 are missense variants that impede the function of certain domains in the b-cardiac myosin heavy chain: for example, the converter domain, actin-binding site and ATP-binding domain (Homburger et al 2016). These pathogenic variants impact protein function via a dominant-negative mechanism (as opposed to loss of function). On the note of loss of function variation in MYH7, there is insufficient evidence at this time to implicate loss of function variants (truncating, frameshift, splice site variants) as causative of HCM. Region-level evidence: Homburger et al 2016: this variant is not enriched in cases over controls in the following domains of b-cardiac myosin heavy chain: spherical, surface or post-stroke spatial configuration This variant is not present in the SHaRe consortium database (current as of 2016) Amr et al 2016: this variant is not significantly enriched in cases of HCM versus controls Case data (not including our patient): 1 ClinVar: Laboratory for Molecular Medicine has seen this vairant in one individual for clinical testing at their lab. They classify it as a VUS. Cases in the literature: none reported We have seen this variant in one patient in our center with DCM, who also had a likely pathogenic variant in TTN. Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "An algorithm developed specifically for the MYH7 gene (PMID: 21310275), suggest that this missense change is likely to be tolerated. However, this prediction has not been confirmed by published functional studies and their clinical significance is uncertain." Conservation data: The threonine at codon 857 is poorly conserved across species. Neighboring amino acids are also poorly conserved. Nearby pathogenic variants at this codon or neighboring codons: Nearby pathogenic variants are reported in ClinVar (Lys847Glu, Glu848del, Met849Thr, Met852Lys,Glu855del); however, none of these variants have been reviewed since the ACMG guidelines on variant interpretation were published. Population data: Highest MAF in European population: 0.0023%. The variant was reported online in 3 of 138,586 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 3 of 63,342 individuals of European descent (MAF=0.0023%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. |