ClinVar Genomic variation as it relates to human health

The c.2206A>G (p.I736V) alteration is located in exon 20 (coding exon 18) of the MYH7 gene. This alteration results from a A to G substitution at nucleotide position 2206, causing the isoleucine (I) at amino acid position 736 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 27532257, 24793961, 32894683, 37652022, 34542152, 25611685, 29300372)

PM1, PM2_supporting, PM5

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 736 of the MYH7 protein (p.Ile736Val). This variant is present in population databases (rs397516138, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961; Invitae). ClinVar contains an entry for this variant (Variation ID: 42889). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant disrupts the p.Ile736 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15856146, 25935763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces isoleucine with valine at codon 736 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 24793961). This variant has been identified in 2/251186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ile736Thr, is known to be disease-causing (ClinVar variation ID: 164342), indicating that isoleucine at this position is important for MYH7 protein function. 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.

This missense variant replaces isoleucine with valine at codon 736 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 24793961). This variant has been identified in 2/251186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ile736Thr, is known to be disease-causing (ClinVar variation ID: 164342), indicating that isoleucine at this position is important for MYH7 protein function. 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.

The p.Ile736Val variant in MYH7 has been reported in the literature in 2 individuals with HCM (Bos 2014; Homburger 2016; Alfares 2015; Walsh 2017). This variant has also been reported in ClinVar (VariationID: 42889). It has been identified in 2/113468 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516138). This variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, the change from isoleucine (Ile) to valine (Val) has been seen in distantly related species. However, a different pathogenic variant involving the same codon (p.Ile736Thr) has been identified in multiple individuals with HCM, suggesting changes at this position may not be tolerated. In addition, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ile736Val variant is uncertain due to conflicting data. ACMG/AMP criteria applied: PS4_supporting, PM5, PM2_Supporting.

This test identified a previously reported variant (c.2206T>C;p.Ile736Val) in the MYH7 gene. This gene is associated with different cardiac conditions including familial hypertrophic cardiomyopathy. The p.Ile736Val variant has been reported in one patient with hypertrophic cardiomyopathy (Bos et al. 2014, PMID: 24793961). Additionally, other variants with different amino acid change (at the same position) have been reported in individuals with familial hypertrophic cardiomyopathy (Koga et al. 1996, PMID: 8951566; Erdmann et al. 2003, PMID: 12974739; Millat et al. 2010, PMID: 20800588).

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.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) The variant has been seen in at least 2 unrelated cases of HCM (not including this patient's family). There is no segregation data available. GeneDx notes that the variant is novel, however I was able to find reports of it online. The variant is listed in ClinVar with a submission from LMM (SCV000059428). The last reviewed in 2008 and classified it as a variant of uncertain significance. It looks like they saw this in one family, though specific phenotypic details are not provided. We have never seen this variant. The variant is also listed online in the Seidmans' database (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_Ile736Val.html), noting their group has seen it in a patient with left ventricular wall thickness of 2.0 cm and a diagnosis of HCM. It is likely that the LMM case and Seidmans' case overlap, given how closely those two groups work together. Dr. Ackerman's group reported the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.996). The isoleucine at codon 736 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile736Thr, which we classify as likely disease causing and p.Ile736Met, p.Ile736Leu) and nearby codons (A728V, A729P, I730T, P731L, P731S, G733R, G733E, Q734E, Q734P, G741A, G741R, G741W, A742E, E743D, per GeneDx report, referencing HGMD). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. There is no variation at codon 736 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). The variant is listed in dbSNP (rs397516138), with the only submission being from LMM (as of July 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bot et al 2014).