ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1106G>A (p.Arg369Gln) (rs397516089)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000587847 SCV000735357 pathogenic Cardiovascular phenotype 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000487437 SCV000564410 likely pathogenic Primary dilated cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1106G>A (p.Arg369Gln) variant in MYH7 has been reported in 6 individuals with dilated cardiomyopathy (PS4_Moderate; PMID:27532257; Partners LMM ClinVar SCV000059349.5; AGCMC Sydney). This variant was been identified as a de novo occurrence in 1 proband with dilated cardiomyopathy (PM6; Partners LMM ClinVar SCV000059349.5). This variant segregated with disease in 2 affected individual (insufficient to meet PP1 criteria; Partners LMM ClinVar SCV000059349.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM1; PM2; PM6; PS4_Moderate
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491937 SCV000298132 likely pathogenic Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided research
GeneDx RCV000223685 SCV000208719 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The R369Q pathogenic variant in the MYH7 gene has been reported in multiple unrelated individuals with cardiomyopathy (Dellefave et al., 2009; Hoedemaekers et al., 2010; Lakdawala et al., 2012; Tian et al., 2015). Dellefave et al. (2009) identified R369Q as a de novo variant in a pediatric patient with heart failure due to dilation and non-compaction of the left ventricle. Lakdawala et al. (2012) also reported R369Q as a de novo variant in two patients with DCM, one of whom harbored another variant in the MYBPC3 gene. Hoedemaekers et al. (2010) identified R369Q in a 10 year-old male with heart failure and LVNC, and Tian et al. (2015) described R369Q in a 13 year-old Chinese male with LVNC. This variant has been identified independently and/or in conjunction with additional cardiogenetic variants in multiple unrelated individuals with DCM referred for testing at GeneDx, and was apparently de novo in one individual based on results of parental testing. The R369Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, this variant is not observed in large population cohorts (Lek et al., 2016).
Integrated Genetics/Laboratory Corporation of America RCV000587847 SCV000696337 pathogenic Cardiovascular phenotype 2017-08-15 criteria provided, single submitter clinical testing Variant summary: The MYH7 c.1106G>A (p.Arg369Gln) variant causes a missense change involving the alteration of a conserved nucleotide located in the P-loop containing nucleoside triphosphate hydrolase domain (IPR027417) (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. This variant was not found in the large control database ExAC and a published study (Lakdawala_TNNT2_J Cardiac Failure_2012) in 122186 control chromosomes. This variant was found in multiple DCM pediatric patients, including de novo occurrences (Walsh_2017, Tian_2015, Lakdawala_2012, Pugh_2014). This variant was also associated with Left ventricular non-compaction (LVNC) in addition to DCM (Dellefave_2009, Hoedemaekers_2010, Tian_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000544985 SCV000623634 pathogenic Hypertrophic cardiomyopathy 2018-02-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 369 of the MYH7 protein (p.Arg369Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs397516089, ExAC no frequency). This variant has been reported in individuals affected with left-ventricular non-compaction cardiomyopathy (PMID: 20530761, 24691700, Invitae) and two individuals affected with dilated cardiomyopathy (PMID: 24503780). This variant has also been shown to arise de novo in an individual affected with left-ventricular non-compaction cardiomyopathy (PMID: 20031619). ClinVar contains an entry for this variant (Variation ID: 42822). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035698 SCV000059349 pathogenic Cardiomyopathy 2014-11-24 criteria provided, single submitter clinical testing The p.Arg369Gln variant in MYH7 has been reported in 1 Chinese child with LVNC (Tian 2014) and has also been identified by our laboratory in 6 individuals (3 with LVNC and 3 with DCM). In two of these cases, the variant occurred de novo (Dellafave 2009, Lakdawala 2012, LMM unpublished data). Additionally, this variant was observed to segregate with disease in 3 affected relatives from 2 families (LMM unpublished data) and was absent from large population studies. Arginine (Arg) at position 369 is highly conserved in mammals and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic for DCM and LVNC in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon multiple de novo occurrences and segregation studies.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223685 SCV000280292 pathogenic not provided 2016-03-29 no assertion criteria provided provider interpretation p.Arg369Gln (R369Q; c.1106G>A) in exon 12 of the MYH7 gene (NM_000257.2) We last reviewed the variant in March 2016. In August 2017 we updated that review to include data from gnomAD. We have seen the variant in two unrelated cases of cardiomyopathy. Given the strong case data, which includes multiple de novo instances, contrasted with the total absence in general population samples, we consider this variant Very Likely Disease Causing and suitable for predictive testing in at-risk family members. This variant has been reported in at least 8 unrelated individuals with DCM or LVNC, at least 3 of them de novo (Dellafave 2009, Lakdawala 2012 using LMM lab). For cases in which the variant was inherited, only weak segregation data is available. It was first reported by Dellefave et al. (2009) from Beth McNally's group in an African American girl with LVNC and acute heart failure at the age of 3.5 years (PubMed: 20031619). Echocardiogram showed a dilated LV with reduced function and fractional shortening of 9.1%. An area of noncompaction in the lateral and posterior section of the LV was seen. EKG showed left atrial enlargement with T-wave inversion on inferior leads. The parents of the patient did not carry the variant, indicating it to be de novo. Lakdawala et al. (using LMM as the sequencing lab) also reported p.Arg369Gln as a de novo variant in two patients with dilated cardiomyopathy (DCM), one Hispanic female diagnosed at age 17 and another individual of unspecified ethnicity. The Hispanic patient also had a missense VUS in MYBPC3: Glu332Lys (PubMed: 22464770; Pugh et al 2014). Hoedemaekers et al (2010) observed the variant in 1 of 58 unrelated individuals with LVNC in their Dutch cohort who underwent sequencing of 17 sarcomere and sarcomere-associated genes in their local clinical genetics lab. The patient was a 10-year-old boy with LVNC and heart failure. No segregation data was reported. The p.Arg369Gln variant has also been reported in 1 Han Chinese boy (age 13) with LVNC and no known family history of cardiomyopathy (Tian et al 2015). Per ClinVar, the LMM laboratory has seen the variant in 6 individuals in total (3 with LVNC and 3 with DCM). In two of these cases (the same cases described in Lakdawala, above), the variant occurred de novo. Additionally, this variant was observed to segregate with disease in 3 affected relatives from 2 families (LMM unpublished data). The arginine at codon 369 is conserved across species, as are neighboring amino acids. In silico analysis with PolyPhen-2 predicts the variant to be benign (with a score of 0.048). By contrast, PolyPhen, SIFT and Mutation Taster predict the variant to be deleterious according to the Blueprint report. It is predicted to be pathogenic using a computational tool developed by LMM using a set of cardiomyopathy variants with well-established clinical significance. This LMM tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). There was no separate published disease-associated variant at the same codon in 2014 (HGMD public version as of 8 Oct 2014, Bos et al 2014 (Mayo 1053 patient series), ClinVar (as of 8 Oct 2014)). Blueprint Genetics does now report seeing another variant at the same codon, p.Arg369Pro, in a 6-year-old girl with features of both DCM and LVNC (ClinVar accession SCV000207091.1). She had symptoms of heart failure. This same variant has also been identified in clinical testing by LMM (ClinVar: SCV000199238.2), who classify it in ClinVar as a VUS after seeing it in 1 case. The variant is not listed 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, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >30x. The variant was not observed in the following published control samples: 172 "healthy controls" (Hoedemaekers et al 2010), ~1200 Caucasian controls ~200 African American controls (Lakdawala N et al., 2012), 307 Chinese controls (Tian et al 2015).

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