ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2570C>T (p.Thr857Ile) (rs397516158)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546729 SCV000623674 uncertain significance Hypertrophic cardiomyopathy 2017-06-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 857 of the MYH7 protein (p.Thr857Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 42917). 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). 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. In summary, this variant has uncertain impact on MYH7 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035806 SCV000059457 uncertain significance not specified 2008-03-01 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University 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.

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