This missense variant replaces arginine with glutamine at codon 970 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 reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in an individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

The p.R970Q variant (also known as c.2909G>A), located in coding exon 28 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2909. The arginine at codon 970 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in individuals with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction (LVNC), but clinical details were limited (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Takasaki A et al. Pediatr Res, 2018 11;84:733-742; Ko C et al. Genet Med, 2018 01;20:69-75; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Identified in several individuals with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 22464770, 24503780, 27532257, 28640247, 30188508, 30847666, 32600061, 35653365, 37652022, 32841044); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24503780, 22464770, 28640247, 30188508, 32600061, 33782553, 35653365, 30847666, 30297972, 34819141, 27532257, 32841044, 37652022)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 970 of the MYBPC3 protein (p.Arg970Gln). This variant is present in population databases (rs727504346, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 22464770, 27532257, 28640247, 30188508, 30297972, 37652022). ClinVar contains an entry for this variant (Variation ID: 177832). 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. 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.

Variant summary: MYBPC3 c.2909G>A (p.Arg970Gln) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 184920 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (5.4e-05 vs 0.001), allowing no conclusion about variant significance. c.2909G>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Lakdawala_2012, Pugh_2014, Walsh_2017, Ko_2018, Ho_2018, Takasaki_2018). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change in MYBPC3 is predicted to replace arginine with glutamine at codon 970, p.(Arg970Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is not located in an annotated domain. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (114/1,160,438 alleles) in the European (non-Finnish) population. This variant has been reported in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction (PMID: 22464770, 27532257, 30847666, 32600061, 32841044). Computational evidence predicts an impact on splicing (SpliceAI) for the nucleotide change, and predicts a benign effect for the missense substitution (REVEL = 0.151). RNA studies have not been conducted to confirm the splicing prediction. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.

The p.Arg970Gln variant in MYBPC3 has been identified in 1 individual with DCM, 2 individuals with HCM, and 1 individual with LVNC (Walsh 2017, Ko 2018, Takasaki 2018, LMM data). It has also been identified in 0.02% (6/28490) of Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #177832). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: None.

The MYBPC3 c.2909G>A; p.Arg970Gln variant (rs727504346) is reported in the literature in several individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, or left ventricular noncompaction, although it was not demonstrated to be disease-causing in these individuals (Helms 2020, Ko 2018, Lakdawala 2012, Takaski 2018, Walsh 2017). This variant is found in the general population with an allele frequency of 0.005% (11/216,302 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.151). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Helms AS et al. Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2020 Oct;13(5):396-405. PMID: 32841044. Ko C et al. Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup. Genet Med. 2018 Jan;20(1):69-75. PMID: 28640247. Lakdawala NK et al. Genetic testing for dilated cardiomyopathy in clinical practice. J Card Fail. 2012 Apr;18(4):296-303. PMID: 22464770. Takasaki A et al. Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction. Pediatr Res. 2018 Nov;84(5):733-742. PMID: 30188508. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.

This missense variant replaces arginine with glutamine at codon 970 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 reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28640247, 30297972, 32841044, 33782553), in one individual affected with dilated cardiomyopathy (PMID: 22464770, 24503780), and in one individual affected with left ventricular noncompaction cardiomyopathy (PMID: 30188508, 32600061). This variant has been identified in 11/216302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.