11-47337544-G-C

Position:

• chr11-47337544-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000256.3(MYBPC3):​c.2449C>G​(p.Arg817Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,692 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R817P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.91

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337544-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164078.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=3}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• PP5: Variant 11-47337544-G-C is Pathogenic according to our data. Variant chr11-47337544-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 810770.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr11-47337544-G-C is described in Lovd as [Pathogenic]. Variant chr11-47337544-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2449C>G	p.Arg817Gly	missense_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2449C>G	p.Arg817Gly	missense_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2449C>G	p.Arg817Gly	missense_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.2414-33C>G		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 23, 2023	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. This variant disrupts the p.Arg817 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26914223, 27532257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 810770). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27600940, 27618852, 28790153, 33782553; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 817 of the MYBPC3 protein (p.Arg817Gly). -
Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Oct 15, 2018	This MYBPC3 Arg817Gly variant has been reported twice before in HCM probands (Galati , et al., 2016; Cecconi M, et al., 2016). This variant is rare and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified the variant in a HCM proband of Middle Eastern decent who was diagnosed in childhood and harbours 2 other variants: MYBPC3 Ala693Val & MYH7 Arg787His (Burns et al., 2019). Computational tools SIFT, MutationTaster, PolyPhen-HCM and PolyPhen-2 predict this variant to have a deleterious effect. A different amino acid change at the same protein position (p.Arg817Gln) has been reported in HCM probands (SCV000059139.4), suggesting that an amino acid substitution at this site may not be tolerated. In summary, based on this evidence we classify MYBPC3 Arg817Gly as a variant of "uncertain significance". -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostCm	Uncertain	0.85
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.80
MVP		0.92
MPC		0.95
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.80
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503188; hg19: chr11-47359095; COSMIC: COSV57022934;