chr11-47342718-C-T

Variant names:

• chr11-47342718-C-T
• rs200411226
• NM_000256.3:c.1484G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM5 PP3 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1484G>A​(p.Arg495Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000198912: "In vitro functional studies suggest that carriers of this variant exhibit heightened expression of MYBPC3 as compared to controls, leading to an abundance of the mutant protein in cardiac tissue." PMID:25031304; SCV004834616: An experimental functional study using a transgenic pig model heterozygous for this variant has shown a phenotype of myocardial fibrosis as well as reduced MYBPC3 expression levels in cardiac fibroblasts (PMID:36357371).; SCV000696312: myocardial tissue obtained from a human HCM subject that harbors the variant show molecular signatures of aberrant calcium signaling (increased Ca2+/Calmodulin dependent protein kinase II (CaMKII) activation and reduced SERCA2 (Sarcoplasmic/endoplasmic reticulum calcuium ATPase 2) mRNA levels, (Helms_2016).; SCV001156327: A study analysing the transcript and protein levels in two septal myectomy patients carrying the MYBPC3 Arg495Gln variant revealed that not only did the patients exhibit a 2-fold increase in MYBPC3 protein expression but were also found to predominately express the mutant peptide (Helms AS, et al., 2014).; SCV000208030: The p.(R495Q) mutant peptide was predominantly expressed compared to wild-type protein in heart tissue specimens from two HCM patients, though the precise correlation to phenotype is yet to be determined (PMID:25031304); SCV001360091: An experimental functional study using a transgenic pig model heterozygous for this variant has shown a phenotype of myocardial fibrosis as well as reduced MYBPC3 expression levels in cardiac fibroblasts (PMID:36357371).; SCV000372358: Helms et al. (2014) demonstrated that heart tissue samples carrying the p.Arg495Gln variant exhibited higher MYBPC3 expression and transcript levels but no increase in protein abundance when compared to control heart tissues.". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R495L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:40
• Conservation: PhyloP100: 5.80
• Publications: 38 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000198912: "In vitro functional studies suggest that carriers of this variant exhibit heightened expression of MYBPC3 as compared to controls, leading to an abundance of the mutant protein in cardiac tissue." PMID:25031304; SCV004834616: An experimental functional study using a transgenic pig model heterozygous for this variant has shown a phenotype of myocardial fibrosis as well as reduced MYBPC3 expression levels in cardiac fibroblasts (PMID: 36357371).; SCV000696312: myocardial tissue obtained from a human HCM subject that harbors the variant show molecular signatures of aberrant calcium signaling (increased Ca2+/Calmodulin dependent protein kinase II (CaMKII) activation and reduced SERCA2 (Sarcoplasmic/endoplasmic reticulum calcuium ATPase 2) mRNA levels, (Helms_2016).; SCV001156327: A study analysing the transcript and protein levels in two septal myectomy patients carrying the MYBPC3 Arg495Gln variant revealed that not only did the patients exhibit a 2-fold increase in MYBPC3 protein expression but were also found to predominately express the mutant peptide (Helms AS, et al., 2014).; SCV000208030: The p.(R495Q) mutant peptide was predominantly expressed compared to wild-type protein in heart tissue specimens from two HCM patients, though the precise correlation to phenotype is yet to be determined (PMID: 25031304); SCV001360091: An experimental functional study using a transgenic pig model heterozygous for this variant has shown a phenotype of myocardial fibrosis as well as reduced MYBPC3 expression levels in cardiac fibroblasts (PMID: 36357371).; SCV000372358: Helms et al. (2014) demonstrated that heart tissue samples carrying the p.Arg495Gln variant exhibited higher MYBPC3 expression and transcript levels but no increase in protein abundance when compared to control heart tissues.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47342718-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 915779.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 11-47342718-C-T is Pathogenic according to our data. Variant chr11-47342718-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 164113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.1484G>A	p.Arg495Gln	missense	Exon 17 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.1484G>A	p.Arg495Gln	missense	Exon 17 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.1484G>A	p.Arg495Gln	missense	Exon 16 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.1484G>A		non_coding_transcript_exon	Exon 17 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249188 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727130

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

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

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000220 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Hypertrophic cardiomyopathy 4 (12)
10	-	-	not provided (10)
5	-	-	Hypertrophic cardiomyopathy (5)
3	-	-	Primary familial hypertrophic cardiomyopathy (3)
2	-	-	Cardiomyopathy (2)
2	-	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (2)
2	-	-	Left ventricular noncompaction 10 (2)
2	-	-	MYBPC3-related disorder (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.43
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Vest4		0.82
MVP		0.89
MPC		0.88
ClinPred		0.82	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.69
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200411226; hg19: chr11-47364269; COSMIC: COSV57022742;