rs200352299
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_000256.3(MYBPC3):c.1855G>A(p.Glu619Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000484 in 1,602,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E619D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 4Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompaction 10Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.1855G>A | p.Glu619Lys | missense_variant | Exon 19 of 35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.1855G>A | p.Glu619Lys | missense_variant | Exon 19 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.1855G>A | p.Glu619Lys | missense_variant | Exon 18 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.1855G>A | non_coding_transcript_exon_variant | Exon 19 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.000342 AC: 52AN: 152166Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000493 AC: 113AN: 229214 AF XY: 0.000539 show subpopulations
GnomAD4 exome AF: 0.000499 AC: 723AN: 1450040Hom.: 0 Cov.: 36 AF XY: 0.000517 AC XY: 372AN XY: 720114 show subpopulations
Age Distribution
GnomAD4 genome 0.000341 AC: 52AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27AN XY: 74472 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Uncertain:2Benign:1
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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. -
not specified Benign:3
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 13.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05). 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 variant(s) have been reported (MYBPC3, p.Ala558lysfsX9; MYBPC3 c.1505G>A , p.R502Q ; MYBPC3, p.L1221fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22857948, 19659763, 23233322, 24093860, 21424860, 19293840, 30871747). ClinVar contains an entry for this variant (Variation ID: 161303). Based on the evidence outlined above, the variant was classified as likely benign. -
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. -
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Left ventricular noncompaction 10 Uncertain:1Benign:1
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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. -
Cardiomyopathy Benign:2
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not provided Benign:2
See Variant Classification Assertion Criteria. -
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 -
Hypertrophic cardiomyopathy Benign:2
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Primary familial hypertrophic cardiomyopathy Uncertain:1
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Cardiovascular phenotype Benign:1
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. -
MYBPC3-related disorder Benign:1
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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at