ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1370T>C (p.Ile457Thr) (rs397516103)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617592 SCV000736144 uncertain significance Cardiovascular phenotype 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000035720 SCV000208736 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing The I457T variant has been reported in at least one Caucasian individual with HCM and was absent from over 200 healthy controls (Fokstuen et al., 2011; Waldmuller et al., 2011). However, detailed clinical, family history and segregation data was not provided. This 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. The I457T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been identified in a significant number of affected individuals, and there are no functional studies or segregation data that would suggest that it is pathogenic.
Invitae RCV000477379 SCV000546249 uncertain significance Hypertrophic cardiomyopathy 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 457 of the MYH7 protein (p.Ile457Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs397516103, ExAC <0.01%). This variant has been reported in several individuals affected with hyperthrophic cardiomyopathy (PMID: 26914223, 28615295, 21750094, 27247418, 29121657, 27532257). ClinVar contains an entry for this variant (Variation ID: 42840). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000477379 SCV000059371 likely pathogenic Hypertrophic cardiomyopathy 2017-08-29 criteria provided, single submitter clinical testing The p.Ile457Thr variant in MYH7 has been reported in at least 9 individuals with HCM (Waldmuller 2011, Fokstuen 2011, Murphy 2016, Walsh 2016, LMM data). This v ariant has been identified in 1/111717 European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397516103). T his variant has been reported in ClinVar (Variant ID: 42840). Isoleucine (Ile) a t position 457 is highly conserved in mammals and across evolutionarily distant species and the change to threonine (Thr) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogen ic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, 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, although additional studies are required to f ully establish its clinical significance, the p.Ile457Thr variant is likely path ogenic.

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