chr11-47343051-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000256.3(MYBPC3):c.1321G>A(p.Glu441Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.1321G>A | p.Glu441Lys | missense_variant | Exon 15 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.1321G>A | p.Glu441Lys | missense_variant | Exon 14 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.1321G>A | non_coding_transcript_exon_variant | Exon 15 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000138 AC: 34AN: 246694Hom.: 0 AF XY: 0.000179 AC XY: 24AN XY: 133988
GnomAD4 exome AF: 0.000118 AC: 173AN: 1460760Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 88AN XY: 726586
GnomAD4 genome 0.000158 AC: 24AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74500
ClinVar
Submissions by phenotype
not provided Uncertain:6Benign:1
Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 18533079, 20173211, 20414521, 20624503, 22765922, 23233322, 26090888, 30871747, 30972196, 37652022, 24093860, 37431535); Observed in individuals with HCM who harbored co-occurring pathogenic cardiogenetic variants; one laboratory reports that an internal patient who also has a pathogenic MYBPC3 variant appeared to have an earlier onset of disease and a more severe presentation relative to the other patients that harbor p.(E441K) in isolation (PMID: 18533079, 20173211, 20624503, 32369506, 37431535; internal GeneDx data; ClinVar SCV000059030.5); Molecular modeling studies suggest that p.(E441K) causes conformational changes in cardiac myosin binding protein-C and interferes with normal binding/unbinding of the N-terminal complex, C1-motif-C2; however, the changes induced by p.(E441K) are less pronounced than those associated with the MYBPC3 p.(E258K) pathogenic variant (PMID: 25971843, 27267291); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25971843, 20173211, 23233322, 23299917, 25637381, 22765922, 20624503, 26090888, 18533079, 27956910, 28518168, 21415409, 25524337, 27267291, 30645170, 30871747, 30731207, 30972196, 28420666, 24093860, 21835320, 20414521, 37652022, 37431535, 32369506, 30446606, 33049255) -
MYBPC3: BP4 -
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BS1, PS3_supporting -
The MYBPC3 c.1321G>A; p.Glu441Lys variant (rs193922377, ClinVar ID: 36601) is reported in the literature in individuals affected with dilated or hypertrophic cardiomyopathy (selected references: Garcia-Molina 2019, Kassem 2013, McGurk 2023, Sousa 2019); however, this variant has also been reported in individuals with pathogenic variant in the same gene (Millat 2010, Olivotto 2008). This variant is found in the general population with an overall allele frequency of 0.015% (41/278,096 alleles) in the Genome Aggregation Database (v2.1.1). In vivo functional analyses in a zebrafish model demonstrate atypical cardiac morphology (Da’as 2018). However, computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.307). Given the inconclusive clinical and functional data, the significance of this variant is uncertain at this time. References: Da'as SI et al. Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction. Biochem J. 2018 Dec 14;475(24):3933-3948. PMID: 30446606. Kassem HSh et al. Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program. J Cardiovasc Transl Res. 2013 Feb;6(1):65-80. PMID: 23233322. GarcÃa-Molina E et al. A study of the pathogenicity of variants in familial heart disease. The value of cosegregation. Am J Transl Res. 2019 Mar 15;11(3):1724-1735. PMID: 30972196. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Millat G et al. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. Eur J Med Genet. 2010 Sep-Oct;53(5):261-7. PMID: 20624503. Olivotto I et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2008 Jun;83(6):630-8. PMID: 18533079. Sousa A et al. Molecular characterization of Portuguese patients with dilated cardiomyopathy. Rev Port Cardiol (Engl Ed). 2019 Feb;38(2):129-139. English, Portuguese. PMID: 30871747. -
Hypertrophic cardiomyopathy 4 Uncertain:4
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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. -
The MYBPC3 Glu441Lys variant has been identified in multiple HCM probands, including several compound heterozygotes (Liu X, et al., 2015; Olivotto I, et al., 2008; Marsiglia JD, et al., 2010; Millat G, et al., 2010; Coto E, et al., 2012; Kassem HSh, et al., 2013, www.cardiodb.org/acgv/). We have identified this variant in 3 probands who were diagnosed at a young age (<18yo) and have severe hypertrophy, with maximum IVS measurements >30mm. All 3 probands also carry a second MYBPC3 variant, and one of these probands also carries a third variant in TNNT2. In one family MYBPC3 Glu441Lys did not segregate to another affected family member. The variant is present in the large Exome Aggregation Consortium dataset at an allele frequency of 0.00016 (http://exac.broadinstitute.org/), which is higher then expected for HCM. In silico tools SIFT, Polyphen2 and MutationTaster predict this variant to be deleterious. In summary, based on the adapted ACMG guidelines (Kelly MA, et al., 2018), the variant does not meet criteria for rarity (PM2) and as a result the identification of the variant in affected probands cannot be used, because only PP3 criteria are met, we classify MYBPC3 Glu441Lys as a variant of "uncertain significance" and suspect the variant may act as a modifier. -
Primary familial hypertrophic cardiomyopathy Uncertain:3
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not specified Uncertain:2
The p.Glu441Lys variant in MYBPC3 has been observed in 10/62060 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922377) and has been reported in at least 9 individuals with HCM, 2 o f whom carried other pathogenic variants (Olivotto 2008, Marsiglia 2010, Millat 2010, Olivotto 2011, Coto 2012, Kassem 2013). Our laboratory has identified this variant in 2 individuals with HCM and 1 individual with biatrial enlargement wh o carried another pathogenic HCM variant. The individual carrying the additional pathogenic HCM variant appeared to have an earlier onset of disease and a more severe presentation relative to the other patients carrying the Glu441Lys varian t. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, the clinical sig nificance of the p.Glu441Lys variant is uncertain. The available data raise the possibility that it is independently disease causing but milder in isolation but additional data is needed to confirm its significance. -
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. MYBPC3 p.Glu441Lys We consider this a variant of uncertain significance. This variant has been seen in at least 7 presumably unrelated individuals with hypertrophic cardiomyopathy (HCM). I was unable to find any reports of this variant with dilated cardiomyopathy. Notably, all of the individuals with this variant had at least one other sarcomere variant. There is no segregation data available on this variant. Olivotto et al. (2008) reported p.Glu441Lys in one patient with HCM who also carried another MYBPC3 variant (p.Glu258Lys). No data regarding phase or severity of phenotype were reported. Millat et al. (2010) reported one individual with HCM who had three variants on one MYBPC3 allele (p.Glu441Lys, p.Gln76Ter, p.Gly279Ala) and also had an additional variant in MYH7 (p.Ile1927Phe). Unfortunately age of onset and severity were not reported. Marsiglia et al (2010) reported the variant in one individual with HCM in Brazil (article is in Portuguese, further details not available). p.Glu441Lys has also been observed in two other unrelated individuals with HCM tested at GeneDx. One individual had two MYBPC3 missense variants and one MYH7 missense variant, was diagnosed with HCM in childhood and required transplant. The other individual was diagnosed with HCM as a child and was a compound heterozygote for this variant and an MYBPC3 frameshift variant (both parents were unaffected). The Seidmans' research group report this variant online in an individual who presumably has HCM and is a compound heterozygote for this variant and p.Glu258Lys (Merk et al 2005, http://genepath.med.harvard.edu/~seidman/cg3/muts/MYBPC3_Glu441Lys.html) This is a semi conservative amino acid substitution of a polar negative Glutamic Acid with a polar positive Lysine. Glutamic Acid is highly conserved at position 441. This variant was not identified in 150 presumably healthy individuals by Olivotto et al (2008). Millat et al (2010) did not do population studies. NHLBI Exome Sequence Variant Database reports p.Glu441Lys in 2 out of 4243 European American individuals and 3 out of 2138 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Based on these data, we consider this variant to be of uncertain significance. This classification is based on the fact that it has primarily (possibly only) been seen in combination with other variants and it has not yet been demonstrated that this variant can cause cardiomyopathy on its own or that it contributes in a significant way when in combination with other variants. -
Cardiomyopathy Uncertain:2
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This missense variant replaces glutamic acid with lysine at codon 441 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20414521, 20624503, 21835320, 22765922, 23233322, 24093860, 26090888, 28420666, 30645170, 30972196, 32369506) or dilated cardiomyopathy (PMID: 30871747). However, some of these individuals also carried pathogenic variants in the same gene that could explain the observed phenotype (PMID: 18533079, 20624503, 32369506). In a study of two families, this variant has been observed in one affected individual but was absent in three other affected individuals (PMID: 30972196). This variant occurs at an appreciable frequency in the general population and has been identified in 41/278096 chromosomes by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals, as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hypertrophic cardiomyopathy Uncertain:2
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 441 of the MYBPC3 protein (p.Glu441Lys). This variant is present in population databases (rs193922377, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic or dilated cardiomyopathy (PMID: 18533079, 20414521, 20624503, 21835320, 22765922, 23233322, 24093860, 26090888, 28420666, 30645170, 30731207, 30871747). ClinVar contains an entry for this variant (Variation ID: 36601). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 30446606). 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. -
This missense variant replaces glutamic acid with lysine at codon 441 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20414521, 20624503, 21835320, 22765922, 23233322, 24093860, 26090888, 28420666, 30645170, 30972196, 32369506), and in individuals affected with dilated cardiomyopathy (PMID: 30871747, 35470680). However, some of these individuals also carried additional pathogenic variants that could explain the observed phenotype (PMID: 18533079, 20624503, 32369506, 37431535). In a study of two families, this variant has been observed in one affected individual but was absent in three other affected individuals (PMID: 30972196). A hypertrophic cardiomyopathy case-control study in Egypt (PMID: 37431535) has reported this variant in 24/514 cases (including 2 homozygotes), 8/400 controls; OR=2.4 (95% CI: 1.0 to 6.2); p-value=0.03. This variant occurs at an appreciable frequency in the general population and has been identified in 41/278096 chromosomes by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals, as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Wolff-Parkinson-White pattern Uncertain:1
This variant was identified in an individual with Wolff-Parkinson-White syndrome -
Left ventricular noncompaction 10 Uncertain:1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Arrhythmogenic right ventricular dysplasia 1 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The c.1321G>A (p.E441K) alteration is located in exon 15 (coding exon 15) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1321, causing the glutamic acid (E) at amino acid position 441 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at