rs397516050

Variant names:

• chr11-47350077-C-T
• rs397516050
• NM_000256.3:c.442G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_000256.3(MYBPC3):​c.442G>A​(p.Gly148Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,561,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict 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. G148E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:10
• Conservation: PhyloP100: 2.89
• Publications: 25 publications found

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47350077-C-T is Pathogenic according to our data. Variant chr11-47350077-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42752.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.442G>A	p.Gly148Arg	missense_variant	Exon 4 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.442G>A	p.Gly148Arg	missense_variant	Exon 4 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.442G>A	p.Gly148Arg	missense_variant	Exon 4 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.442G>A		non_coding_transcript_exon_variant	Exon 4 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000650 AC: 11 AN: 169270 AF XY: 0.0000555

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 156 AN: 1409080 Hom.: 0 Cov.: 35 AF XY: 0.0000991 AC XY: 69 AN XY: 696094

African (AFR) AF: 0.00 AC: 0 AN: 32062

American (AMR) AF: 0.00 AC: 0 AN: 37066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 36536

South Asian (SAS) AF: 0.00 AC: 0 AN: 79834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.000139 AC: 151 AN: 1084430

Other (OTH) AF: 0.0000856 AC: 5 AN: 58388

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000939 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000434 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:6 Uncertain:4

Dec 02, 2017

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25210889, 22267749, 18409188, 20474083, 20530761, 30291343, 25335496, 27650965, 20378854, 23861362, 27532257, 28794111, 28679633, 28790153, 29988065, 29447731, 29121657, 29709087, 31293105, 30847666, 32480058, 33662488, 35288587, 36243179, 33782553, 36264615, 37652022) -

Sep 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.442G>A; p.Gly148Arg variant (rs397516050) is reported in the literature in at least 19 unrelated individuals with cardiomyopathy, some of whom harbored additional uncertain or pathogenic variants in MYBPC3 or other genes associated with cardiomyopathy (Alfares 2010, Burns 2017, Page 2012, van Velzen 2017, van Waning 2018, Viswanathan 2017, Walsh 2017, Zimmerman 2010). This variant also segregated with disease in seven individuals from two families, including four individuals with childhood onset of cardiomyopathy who were also compound heterozygous for a second pathogenic variant in MYBPC3 (Hoedemaekers 2010, Saltzman 2010). This variant is predicted to create a cryptic splice acceptor site (Alamut v.2.11), which is supported by a functional mini-gene assay (Ito 2017); however, the physiological relevance of these observation is unknown. This variant is reported in ClinVar (Variation ID: 42752) and is found in the non-Finnish European population with an allele frequency of 0.015% (13/83,936 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered likely pathogenic. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 18, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 09, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM3, PS3_supporting, PS4 -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: PS3:Moderate, PS4:Moderate, PM2:Supporting, PP1, PP3 -

Hypertrophic cardiomyopathy 4 Pathogenic:5 Uncertain:3

Jun 05, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This MYBPC3 Gly148Arg variant has previously been identified in association with HCM (Genedx, pers. comm., May 2017; LMM, pers. comm.; Meinke P, et al., 2014; Page SP, et al., 2012; Saltzman AJ, et al., 2010), Anderson Fabry disease (Page SP, et al., 2012) and LVNC (Hoedemaekers YM, et al., 2010). Two studies identified an additional variant known to be pathogenic in the families, although both families demonstrate that Gly148Arg alone may cause HCM (Saltzman AJ, et al., 2010; Hoedemaekers YM, et al., 2010). We have identified the variant in 2 HCM probands. MYBPC3 Gly148Arg has been observed resent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0000665, which is higher than expected for disease-causing HCM variants. The variant is also present in 2 of 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts (Bick AG, et al., 2012). This missense variant is predicted to be benign by in silico tools (SIFT, PolyPhen-HCM, MutationTaster, CADD). In summary the variant has been identified in numerous HCM probands, however due to the relatively high frequency in the general population these finding may be coincidental, furthermore in silico tools predict this variant to be benign, therefore due to the conflicting evidence we classify MYBPC3 Gly148Arg as a variant of "uncertain significance". -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3: 16 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in HCM patients and a single ARVC patient, some of whom harboured other possibly causative variants. It has also been reported as a VUS in an individual with HCM who also harboured a causative de novo variant in FHL1. Familial cases of HCM and/or LVNC were also reported where compound heterozygotes presented with a severe, early onset condition while heterozygotes were either asymptomatic or only mildly affected. Finally, this variant has also been reported in cases of sudden death (ClinVar, VCGS, PMIDs: 27532257, 29988065, 30847666, 29709087, 20530761, 20378854, 22267749, 31293105, 27650965, 33495597, 33732734, 33662488, 34389451, 35288587). (I) 0902 - This variant has moderate evidence for segregation with disease, having segregated within three independent families (personal communication). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 19, 2024

North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_Mod PS3_Mod PS4_Mod -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2017

Phosphorus, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2024

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:2

Apr 02, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G148R variant (also known as c.442G>A), located in coding exon 4 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 442. The glycine at codon 148 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in cohorts or patients with various cardiovascular phenotypes including hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), arrhythmogenic right ventricular cardiomyopathy (ARVC), and dilated cardiomyopathy (DCM), and has been reported in families, frequently co-occurring with additional alterations in MYBPC3 and other cardiac-related genes where compound heterozygous cases have presented with severe or early-onset phenotype (Hoedemaekers YM et al. Circ Cardiovasc Genet. 2010;3(3):232-9; Saltzman AJ et al. Circ Res. 2010;106(9):1549-52; Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66; Meinke P et al. PLoS Genet. 2014;10(9):e1004605; van Velzen HG et al. Circ Cardiovasc Genet. 2017;10(4); van Waning JI et al. J Am Coll Cardiol. 2018;71(7):711-722; Te Rijdt WP et al. Cardiovasc Pathol. 2019;40:2-6; Alimohamed MZ et al. Int J Cardiol, 2021 06;332:99-104). In one or more case control studies, this variant was found to be associated with MYBPC3-related hypertrophic cardiomyopathy (McGurk KA et al. Am J Hum Genet, 2023 Sep;110:1482-1495; Meisner JK et al. Circulation, 2025 Mar;151:783-798). Functional studies in patient-derived induced pluripotent stem cells suggest this variant causes myocyte hypertrophy and sarcomere disorganization; however, the physiological relevance of these findings are unclear (Kinnear C et al. Cell Rep Med, 2024 May;5:101520). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect in the set of samples tested (Ambry internal data; Meisner JK et al. Circulation, 2025 Mar;151:783-798). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, this variant likely exhibits low penetrance in the heterozygous state and may represent a risk factor that manifests clinically only in the presence of additional genetic or environmental factors. -

Jan 20, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PVS1_mod, PM2, PP1_mod -

Cardiomyopathy Pathogenic:1 Uncertain:1

Apr 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 148 of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587, 38489124). At least 4 of these individuals carried another pathogenic variant (PMID: 20378854, 20530761, 22267749, 30763825, 35288587; ClinVar SCV000059278.6); in some of these individuals, phenotype was severe (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with disease in 6 heterozygous individuals from 3 families (PMID: 20378854, 20530761, 35288587). This variant has been observed in unaffected individuals (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European; 0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance. -

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:2

Sep 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 148 in the proline-rich domain of the MYBPC3 protein in a region that is poorly conserved across mammalian species. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools indicate that this variant may activate a cryptic splice acceptor site 37 nucleotides downstream of the intron 3 native splice acceptor site. Although this variant has been reported to adversely impact splicing based on a mini-gene assay, its exact molecular consequence was not clearly described and actual data were not available for evaluation (PMID: 28679633, 29709087). This variant has been reported in at least 19 unrelated individuals affected with hypertrophic cardiomyopathy from at least ten different families (PMID: 20378854, 22267749, 25210889, 27532257, 29121657, 32369506, 33495596, 33662488, 34389451, 35288587). At least 4 of these affected individuals carried another pathogenic variant in the same gene or a different gene (PMID: 20378854, 20530761, 22267749, 30763825, 35288587; ClinVar SCV000059278.6); in some of these individuals, phenotype was severe or early-onset (PMID: 20378854, 20530761, 22267749, 35288587). This variant has been shown to segregate with hypertrophic cardiomyopathy in six heterozygous individuals from three families (PMID: 20378854, 20530761, 35288587). This variant has been observed in individuals lacking a hypertrophic cardiomyopathy phenotype (PMID: 20530761, 23861362, 31293105). This variant has also been identified in 13/200668 chromosomes (13/83936 Non-Finnish European; 0.0154%) in the general population by the Genome Aggregation Database (gnomAD). In summary, the molecular impact of this variant on the MYBPC3 gene function is not clearly understood. While this variant has been observed in multiple individuals affected with hypertrophic cardiomyopathy, some of these individuals carried different variants that could be causal for the observed phenotype. This variant is observed at an elevated frequency in the general population and has also been reported in unaffected individuals in the literature. Although there is a suspicion that this variant may play a role in disease, the available evidence is insufficient to determine the pathogenicity of this variant conclusively. Therefore, this variant has been classified as a Variant of Uncertain Significance. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 148 of the MYBPC3 protein (p.Gly148Arg). This variant is present in population databases (rs397516050, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM), left ventricular noncompaction cardiomyopathy (LVNC) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20378854, 20530761, 22267749, 25210889, 27532257, 29661763, 29709087, 30763825, 30847666, 32369506, 32480058, 32588587, 37652022). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42752). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Jan 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.442G>A (p.Gly148Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 169270 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (6.5e-05 vs 0.001), allowing no conclusion about variant significance. c.442G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Left Ventricular Noncompaction Cardiomyopathy (Fokstuen_ 2008, Hoedemaekers_2010, Saltzman_2010, Page_2012, Sabater-Molina_2013, Christiansen_2016, Burns_2017, van Velzen_2017, Walsh_ 2017, Viswanathan_2018, Alimohamed_2021, Lesurf_2022). These data indicate that the variant is likely to be associated with disease. 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: 33662488, 28790153, 27650965, 18409188, 20530761, 28679633, 35288587, 22267749, 20378854, 29121657, 27532257, 29661763). ClinVar contains an entry for this variant (Variation ID: 42752). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

MYBPC3-related disorder Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYBPC3 c.442G>A variant is predicted to result in the amino acid substitution p.Gly148Arg. This patient is heterozygous in the MYBPC3 gene for a sequence variant designated c.442G>A, which is predicted to result in the amino acid substitution p.Gly148Arg. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy or sudden unexplained death (Page et al. 2012. PubMed ID: 22267749; Meinke et al. 2014. PubMed ID: 25210889; Christiansen. 2016. PubMed ID: 27650965; Burns. 2017. PubMed ID: 28790153; Walsh. 2017. PubMed ID: 27532257). Additionally, this variant has been found to be in trans with a second MYBPC3 variant and segregated with hypertrophic cardiomyopathy in several family members who were heterozygous for only the c.442G>A variant (Hoedemaekers et al. 2010. PubMed ID: 20530761; Saltzman et al. 2010. PubMed ID: 20378854; van Velzen. 2017. PubMed ID: 28794111; van Waning. 2018. PubMed ID: 29447731). In silico tools and RNA sequencing data indicate this variant may impact splicing (Supplemental dataset 6 - Ito. 2017. PubMed ID: 28679633). This variant has conflicting interpretations of pathogenicity of uncertain and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42752/). Based on the available evidence, we consider the MYBPC3 c.442G>A variant to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
CardioboostCm	Benign	0.0015
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PhyloP100		2.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.040	B;.;.
Vest4		0.20
MutPred		0.23		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.46
MPC		0.32
ClinPred		0.071	T
GERP RS		1.2
Varity_R		0.059
gMVP		0.23
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516050; hg19: chr11-47371628;