rs397516050

chr11-47350077-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 15/24 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:11 U:10
• Conservation: PhyloP100: 2.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 id is 42752.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=10, Pathogenic=2, Likely_pathogenic=6}. Variant chr11-47350077-C-T is described in Lovd as [Pathogenic]. Variant chr11-47350077-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.442G>A	p.Gly148Arg	missense_variant	4/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.442G>A	p.Gly148Arg	missense_variant	4/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.442G>A	p.Gly148Arg	missense_variant	4/34	5		A2
MYBPC3	ENST00000544791.1	c.442G>A	p.Gly148Arg	missense_variant, NMD_transcript_variant	4/27	5

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

GnomAD3 exomes AF: 0.0000650 AC: 11 AN: 169270 Hom.: 0 AF XY: 0.0000555 AC XY: 5 AN XY: 90100

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.0000856

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000434 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:5

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 09, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MYBPC3: PP3, PP4, PS3:Supporting, PS4:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 02, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	In silico analysis supports a deleterious effect on splicing; In silico analysis supports 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, 33782553, 33662488, 35288587) -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2022	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2019	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. -

Hypertrophic cardiomyopathy 4 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

Hypertrophic cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jun 05, 2018	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". -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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, 29709087, 30847666, 32480058, 32588587). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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. -

Primary familial hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Cardiomyopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 03, 2023	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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.442G>A (p.G148R) alteration is located in exon 4 (coding exon 4) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 442, causing the glycine (G) at amino acid position 148 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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;.;.
MutationTaster	Benign	1.0	N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516050; hg19: chr11-47371628;