ClinVar Genomic variation as it relates to human health

p.Glu619Lys in exon 19 of MYBPC3: This variant has been previously identified i n >10 individuals with varying cardiomyopathies including DCM, HCM, LVNC, and WP W (Moller 2009, Frisso 2009, Brito 2012, Kassem 2013, LMM unpublished data); how ever, at least three of these individuals carry an additional disease-causing va riant. Furthermore, this variant did not segregate with disease in 3 affected re latives (LMM unpublished data, pers. comm.). This variant has also been identifi ed in 0.1% (41/30772) European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org/; dbSNP rs200352299). Lastly, glutamic acid (Glu) at position 619 is not conserved in mammals or evolutionarily distant spe cies and the change to lysine (Lys) was predicted to be benign using a computati onal tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, the presen ce of this variant in different cardiomyopathies, non-segregation, and frequency in the general population support that this variant is likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: MYBPC3 c.1855G>A (p.Glu619Lys) results in a conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 229814 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1855G>A has been reported in the literature in individuals affected with both Dilated and Hypertrophic Cardiomyopathy (Chung_2007, Moller_2009, Kassem_2013, Brito_2012, Marsiglia_2013, Sousa_2019). Co-occurrences with other pathogenic variants have been reported (MYBPC3, p.Ala558lysfsX9; MYBPC3 c.1505G>A , p.R502Q ; MYH7 c.1988G>A, p.R663H ; MYBPC3, p.L1221fs), providing supporting evidence for a benign role (Kassem_2013, Brito_2012, Marsiglia_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=9) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

p.Glu619Lys (c.1855 G>A) in MYBPC3 (NM_000256.3) We briefly re-reviewed this variant in April 2017, focusing on gnomAD and ClinVar. We did not re-assess case data. GeneDx initially classified the variant as a known disease-causing mutation, then a variant of uncertain significance, now likely benign. Given the frequency in reference samples (including 0.56% of Ashkenazi Jews), frequent co-occurrence with other pathogenic variants, and the fact that many cases are Ashkenazi Jewish, we consider this variant likely benign. ClinVar classifications (as of April 19, 2017): benign (Invitae), likely benign (GeneDx, LMM). The variant has been seen in multiple cases of HCM and DCM however many of them had another pathogenic variant. Frisso et al (2009) first reported the variant in one of 39 patients with pediatric onset HCM recruited from the South of Italy (more specific ancestry is not reported). They analyzed 8 sarcomere genes. Moller et al (2009) observed the variant in two brothers with dilated cardiomyopathy from their Danish cohort of 31 patients with dilated cardiomyopathy (more specific ancestry is not reported). Brito et al (2012) observed the variant in two unrelated patients with HCM from their Portuguese cohort of 77 HCM patients who underwent analysis of 5 sarcomere genes (again, specific individual ancestry was not provided). One patient was a compound heterozygote for this variant and p.Arg502Gln in MYBPC3, which we classify as very likely disease causing. While they note that these patients had a family history of HCM they unfortunately do not provide any segregation data. Kassem et al (2012) reported two of 192 Egyptian patients with cardiomyopathy who had sequencing of MYBPC3, MYH7, and TNNT2. One patient was a compound heterozygote for this variant and for p.Ala558lysfsX9, which we have not reviewed but would classify as either likely or very likely disease causing based on strong evidence that frameshift variants in MYBPC3 cause disease. Another patient carried only p.Glu619Lys and had left ventricular non-compaction without left ventricular hypertrophy. The Seidmans' online database notes a direct submission to them by Peng et al, with no phenotypic data provided (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYBPC3_Glu619Lys.html). Marsiglia et al (2013) observed the variant in one of 268 HCM patients from their Brazilian cohort who underwent analysis of MYH7, MYBPC3, and TNNT2. This patient was a compound heterozygote for this variant and a frameshift variant. The variant is not listed in ClinVar. Internal case data from the genetic testing labs suggests the variant may not be pathogenic and may be more prevalent in Ashkenazi Jews. Specifically, the Glu619Lys variant has been identified in multiple families tested for HCM or DCM at GeneDx, and approximately one third of these families identified themselves as having an Ashkenazi Jewish background. Additionally, approximately one third of the families found to harbor the Glu619Lys variant also carried a separate disease-causing mutation associated with cardiomyopathy, suggesting that Glu619Lys may not be a primary disease-causing mutation on its own. The Gly619Lys variant has also been detected in multiple individuals referred for HCM or DCM testing at the Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, and approximately half of these patients were reportedly of Ashkenazi Jewish background (personal communication to GeneDx from H. Rehm), again suggesting that Glu619Lys may be a common variant in the Ashkenazi Jewish population. One of the LMM families is described in Ball et al (2012). In a publication by LMM on their broad DCM panel, they describe a 19yo woman with DCM and a family history of DCM who carries this variant. Ancestry is noted as White. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.426). The glutamic acid at codon 619 is not completely conserved across species. I could find no other variants reported in association with disease at this codon and only one at nearby codons (p.Pro608Leu). The Grantham score is 56. The variant was reported online in 121 of 128,731 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. The highest freqency is in Ashkenazi Jews: 54 of 4,861 individuals of Ashkenazi descent (MAF 0.56%). 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. The variant was not observed in the following published control samples: 200 Caucasians with normal ECGs (Frisso et al 2009), 100 randomly selected Danish individuals (Moller et al 2009) 100 Egyptians (Kassem et al 2012). Bick et al (2012) reported the variant in two of 1637 individuals in the Framingham Heart study with left ventricular wall thicknesses of 1.01 cm and 1.04 cm.

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).