ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.709C>T (p.Arg237Trp) (rs45516091)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157351 SCV000059645 pathogenic Primary dilated cardiomyopathy 2015-04-22 criteria provided, single submitter clinical testing The p.Arg237Trp variant in MYH7 has been previously identified by our laboratory in 1 adult with DCM and segregated with disease in 6 affected relatives from 1 family including 1 obligate carrier and 1 individual with an enlarged LV. This v ariant has also been reported in the literature in 1 individual with DCM (Hershb erger 2008). This variant has been identified in 1/11608 of Latino chromosomes b y the Exome Aggregation Consortium (ExAC,; dbSNP rs45516091). Please note that for diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the genera l population. Computational prediction tools and conservation analysis suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, this variant meets our criteri a to be classified as pathogenic for DCM in an autosomal dominant manner (http:/ / based on segregation studies and ex tremely low frequency in controls.
GeneDx RCV000158879 SCV000208814 likely pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing The R237W variant was initially reported in one individual with familial DCM who also harbored a possibly disease-causing LDB3 variant (Hershberger et al., 2008). Subsequently, R237W was identified in a patient with DCM who harbored a co-occurring truncating TTN variant (Franaszczyk et al., 2017). The R237W variant is also classified in ClinVar as a likely pathogenic or pathogenic variant by external clinical laboratories, one of which reports that R237W was identified by their laboratory in one adult with DCM and segregated with disease in six affected relatives from one family (SCV000059645.4; SCV000318928.1; Landrum et al., 2016). Furthermore, R237W has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). In addition, this 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Ambry Genetics RCV000252658 SCV000318928 likely pathogenic Cardiovascular phenotype 2020-01-24 criteria provided, single submitter clinical testing ​The p.R237W variant (also known as c.709C>T) is located in exon 8 (coding exon 6) of the MYH7 gene. This alteration results from a C to T substitution at nucleotide position 709. The arginine at codon 237 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the myosin head domain. This alteration occurred de novo in a proband tested by our laboratory with hypertrophic cardiomyopathy (internal data). In addition, this variant has been reported in individuals with familial dilated cardiomyopathy (DCM) who also carried variants in the LDB3 or TTN genes (Hershberger RE et al. Clin Transl Sci. 2008 1:21-6; Franaszczyk M et al. PLoS ONE. 2017;12(1):e0169007), and has been detected in additional DCM cohorts (Dal Ferro M et al. Heart. 2017;103(21):1704-1710). Functional studies suggest this variant may alter myosin force generation capacity; however, the physiological relevance is unclear (Ujfalusi Z et al. Biol Chem. 2018;293(23):9017-9029). Another variant affecting this codon (p.R237Q, c.710G>A) has been detected in a cardiomyopathy genetic testing cohort (Walsh R et al. Genet. Med. 2017;19(2):192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000811971 SCV000952268 uncertain significance Hypertrophic cardiomyopathy 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 237 of the MYH7 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs45516091, ExAC 0.009%). This variant has been observed in several individuals affected with dilated cardiomyopathy (PMID: 19412328, 28416588, 27532257); one of these individuals had additional variants in cardiomyopathy-related genes. ClinVar contains an entry for this variant (Variation ID: 43098). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852457 SCV000995150 pathogenic Cardiomyopathy 2018-04-23 criteria provided, single submitter clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV001265607 SCV001443153 likely pathogenic See cases 2020-11-16 criteria provided, single submitter clinical testing We observed the c.709C>T (p.R237W) variant in a 62-y.o. female proband, diagnosed with left ventricular non-compaction, arrhythmogenic right ventricular dysplasia and dilatation of cardiac chambers. The c.709C>T (p.R237W) variant is a known rare variant with frequency approx. 1.193e-5 (gnomAD). It was previously described in the patients with DCM. Its functional impact was shown in the studies of Liu et al (2018) and Ujfalusi et al (2018). Additionally, it should be noted that the p.R237W variant is a missense variant in MYH7 gene with z-score of 3.93 (gnomAD), therefore, MYH7 gene is likely to be intolerant of missense changes. In silico programs (PolyPhen2, MutationTaster, SIFT) also classify the p.R237W variant as probably pathogenic. Based on the evidence, we classify the c.709C>T (p.R237W) variant as likely pathogenic. The c.709C>T (p.R237W) variant was observed in combination with the p.Q1233* variant in MYBPC3 gene. Both variants were at heterozygous state.
Blueprint Genetics RCV000157351 SCV000207088 likely pathogenic Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223687 SCV000280375 uncertain significance not specified 2014-12-23 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.Arg237Trp in MYH7. We classify it as a variant of uncertain significance, concluding that there is insufficient data to determine whether this variant causes cardiomyopathy. This variant has been published in two individuals with DCM and also observed by GeneDx in one DCM patient from Stanford and in another individual with cardiomyopathy. One of the published DCM cases also harbored a likely disease-causing variant in LDB3 (Hershberger et al, 2008). The other published DCM case (a Caucasian male with a family history of DCM) from the Laboratory for Molecular Medicine had multiple additional variants of unknown significance in the ACTN2, CTF1, and TTN genes (Pugh et al, 2014). The lab reports in ClinVar that it segregated with disease in 1 affected relative. LMM classifies it as a variant of unknown significance. p.Arg237Trp results in a non-conservative amino acid change with replacement of a hydrophilic Arginine with a hydrophobic Tryptophan residue at a position that is highly conserved across vertebrate species throughout evolution (it is a Cysteine in the turkey). In silico analysis (PolyPhen2) predicts this change to be probably damaging to the structure/function of the protein. SIFT predicts it to be deleterious. Variants at nearby residues (p.Leu227Val, Asn232Ser, p.Ala233Ser, p.Thr235Asn, p.Val236Ile, p.Asp239Asn, Arg243Cys, Arg243His, Phe244Leu, Lys246Gln, Phe247Leu) have been reported in association with hypertrophic cardiomyopathy or, more rarely, dilated cardiomyopathy. This variant has been seen in 1 Hispanic individual from ~60,000 total published controls and individuals from publicly available population datasets. It was not identified by Hershberger et al. in 253 control samples of varying ethnic backgrounds. The variant is not currently listed in the NHLBI Exome Sequence dataset (as of 6/10/2015), which includes ~6500 Caucasian and African-American individuals. It is not present in 1000 Genomes. The variant is listed in dbSNP (rs45516091), however the only submitted data seems to be that it was not observed in 16 Asian, 16 Hispanic, 181 Caucasian, 22 African American individuals from Corriel. Our patient’s ancestry is Hispanic. Ancestry-matched individuals can be found in greater numbers in the ExAC database of 60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC currently contains 5789 “Latino” individuals. There is only 1 individual in ExAc with this variant, and that person is Latino.

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