ClinVar Genomic variation as it relates to human health

The NM_000257.4(MYH7):c.1106G>A (p.Arg369Gln) variant has been identified in >20 individuals with DCM, including 1 individual who also had LVNC (PS4; Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID:24503780; Klauke 2017 PMID: 29253866; Walsh 2017 PMID: 27532257; Horvat 2019 PMID: 29892087; Quiat 2020 PMID: 32458740; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; Mayo clinic pers. comm.; OMGL pers comm.) and at least 2 individuals with assumed de novo occurrences (PM6; Lakdawala 2012 PMID: 22464770; Quiat 2020 PMID: 32458740; Klauke 2017 PMID: 29253866; LMM pers. comm.). This variant was also identified in >10 individuals with isolated LVNC, including 1 with an assumed de novo occurrence (Dellefave 2009 PMID: 20031619; Hoedemaekers 2010 PMID: 20530761; Tian 2015 PMID: 24691700; Li 2018 PMID: 30371277; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm). This variant segregated with DCM in at least 3 affected individuals from 3 families (PP1; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.), and with LVNC in at least 5 individuals from 4 families (Centenary Institute Sydney pers. comm.; LMM pers. comm.; OMGL pers. comm.) . This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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 (Kelly 2018 PMID:29300372): PS4, PP1, PM6, PM2.

Reported in multiple unrelated individuals with cardiomyopathy, including several pediatric patients (Dellefave et al., 2009; Hoedemaekers et al., 2010; Lakdawala et al., 2012; Tian et al., 2015; Walsh et al., 2017; Horvat et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a likely pathogenic variant by the ClinGen Inherited Cardiomyopathy Expert Panel; classified as pathogenic by several clinical laboratories and reported by one laboratory to segregate with disease in three affected relatives from two families (ClinVar SCV000564410.4; SCV000059349.5; ClinVar); This variant is associated with the following publications: (PMID: 24691700, 20530761, 24503780, 22464770, 20031619, 27066506, 27532257, 28606303, 29300372, 29892087, 18519860, 29253866, 32458740, 34426522, 33500567, 27535533, 26582918)

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

This variant has been previously reported as a heterozygous inherited and de novo change in patients with left ventricular non-compaction, dilated cardiomyopathy and heart failure (PMID: 20031619, 24503780, 24691700, 27532257, 29892087, 32458740). This variant is located in a region of the protein that is enriched with disease-causing missense alterations (PMID: 27532257). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1106G>A (p.Arg369Gln) variant is classified as Pathogenic.

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.

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 wi th LVNC and 3 with DCM). In two of these cases, the variant occurred de novo (De llafave 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 (Ar g) at position 369 is highly conserved in mammals and the change to glutamine (G ln) was predicted to be pathogenic using a computational tool clinically validat ed by our laboratory. This tool's pathogenic prediction is estimated to be corre ct 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 (h ttp://www.partners.org/personalizedmedicine/LMM) based upon multiple de novo occ urrences and segregation studies.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 369 of the MYH7 protein (p.Arg369Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with left-ventricular non-compaction cardiomyopathy and dilated cardiomyopathy (PMID: 20031619, 20530761, 24503780, 24691700; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42822). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

The p.R369Q pathogenic mutation (also known as c.1106G>A), located in coding exon 10 of the MYH7 gene, results from a G to A substitution at nucleotide position 1106. The arginine at codon 369 is replaced by glutamine, an amino acid with highly similar properties, and is located in the head domain. This alteration has been detected in individuals reported to have left ventricular non-compaction and individuals reported with dilated cardiomyopathy; the alteration has also been reported as occurring in an apparent de novo state in affected individuals and also has shown segregation with disease in families (Dellefave LM et al. Circ Cardiovasc Genet. 2009;2(5):442-9; Lakdawala NK et al. J Card Fail. 2012;18(4):296-303; Tian T et al. Heart Vessels. 2015;30(2):258-64; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Horvat C et al. Genet Med. 2019 01;21(1):133-143). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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).