11-47338520-C-T

Position:

• chr11-47338520-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2308G>A​(p.Asp770Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D770E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 16 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, 9 uncertain in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47338520-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407327.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47338520-C-T is Pathogenic according to our data. Variant chr11-47338520-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47338520-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-47338520-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2308G>A	p.Asp770Asn	missense_variant, splice_region_variant	23/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2308G>A	p.Asp770Asn	missense_variant, splice_region_variant	23/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2308G>A	p.Asp770Asn	missense_variant, splice_region_variant	22/34	5		A2
MYBPC3	ENST00000544791.1	c.2308G>A	p.Asp770Asn	missense_variant, splice_region_variant, NMD_transcript_variant	23/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 249118 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000791 Hom.: 0

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 11, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); Published expression studies revealed the absence of mutant transcript and peptide in a myocardial sample from a patient harboring this variant, providing evidence that c.2308 G>A leads to mRNA degradation (Helms et al., 2014); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 33906374, 34097875, 34011823, 31722741, 15519027, 18273486, 18533079, 23054336, 22555271, 16858239, 24111713, 27483260, 24510615, 27532257, 28138913, 28658286, no PMID, 28916354, 28971120, 28771489, 28679633, 29540445, 25351510, 27688314, 26090888, 25740977, 30984009, 31006259, 29997392, 30645170, 31589614, 32746448, 33190526, 25031304) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 4 Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Jan 31, 2020	This variant has been reported in the literature in multiple individuals with hypertrophic cardiomyopathy (Van Driest 2004, Girolami 2006, Tanjore 2008, Olivotto 2008, Kindel 2012, Berge 2014, Calore 2015). This variant has an overall allele frequency of 0.000016 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. This variant has also been reported in the literature to impact splicing (Helms 2014). Thus, this variant is interpreted as pathogenic. PS4-moderate; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 17, 2022	PS3, PS4, PM2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jan 01, 2016	- -

Hypertrophic cardiomyopathy Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 770 of the MYBPC3 protein (p.Asp770Asn). This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon. This variant is present in population databases (rs36211723, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15519027, 18273486, 18533079, 22555271, 24111713, 25740977, 28356264). ClinVar contains an entry for this variant (Variation ID: 36604). 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. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 25031304). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 27, 2018	The p.Asp770Asn variant in MYBPC3 has been reported in >15 individuals with HCM and segregated with disease in one affected relative (Helms 2014, Girolami 2006, McNamara 2017, Olivotto 2008, Tanjore 2008, Van Driest 2004, Walsh 2016, LMM da ta, GeneDx pers comm). It has also been identified in 4/246120 chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s36211723). This variant is located in the last base of exon 23, which is part o f the 5? splice region and computational tools predict an impact on splicing. Ex amination of cardiac tissue from a patient with HCM who carried this variant sho wed a severe impact on splicing leading to nonsense mediated decay (Helms 2014). Heterozygous loss of function of the MYBPC3 gene is an established disease mech anism in individuals with HCM. In summary, this variant meets criteria to be cla ssified as pathogenic for HCM in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PS3, PM2. -
Uncertain significance, flagged submission	research	Genetics and Genomics Program, Sidra Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2023	This missense variant changes the last nucleotide c.G of exon 23 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 23 splice donor site. A study has shown that both variant transcript and resulting truncated protein were undetectable in myocardial samples from a carrier individual (PMID: 25031304), consistent with the expected degradation of the aberrant transcript by nonsense-mediated RNA decay. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 18273486, 18533079, 23054336, 24111713, 27483260, 27532257, 27688314, 28138913, 28356264, 28658286, 28824454, 28971120, 34137518). This variant has been identified in 4/249118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Left ventricular noncompaction 10 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	KTest Genetics, KTest	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 22, 2022

This missense variant changes the last nucleotide c.G of exon 23 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 23 splice donor site. A study has shown that both variant transcript and resulting truncated protein were undetectable in myocardial samples from a carrier individual (PMID: 25031304), consistent with the expected degradation of the aberrant transcript by nonsense-mediated RNA decay. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 18273486, 18533079, 23054336, 24111713, 27483260, 27532257, 27688314, 28138913, 28356264, 28658286, 28824454, 28971120, 34137518). This variant has been identified in 4/249118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Conduction disorder of the heart Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 15, 2021

Variant summary: MYBPC3 c.2308G>A (p.Asp770Asn) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Helms_2014). The variant allele was found at a frequency of 2e-05 in 250492 control chromosomes. c.2308G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. VanDriest_2004, Girolami_2006, Kindel_2012, Berge_2013, Helms_2014). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

The c.2308G>A pathogenic mutation (also known as p.D770N), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2308. This change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the aspartic acid at codon 770 to asparagine, an amino acid with some highly similar properties. This alteration has been reported in a number of individuals from varying ethnic backgrounds with hypertrophic cardiomyopathy (Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Tanjore RR et al. Can J Cardiol. 2008;24(2):127-30; Olivotto I et al. Mayo Clin Proc. 2008;83(6):630-8; Kindel SJ et al. J Card Fail. 2012;18(5):396-403; Miller EM et al. J Genet Couns. 2013;22(2):258-67; Berge KE and Leren TP. Clin Genet. 2014;86(4):355-60). In one study, mutant transcript containing this variant was not detected, indicating this alteration may cause aberrant splicing that could lead to haploinsufficiency (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). In addition, this alteration was suggested to impact calcium handling (Helms AS et al. Circulation. 2016;134(22):1738-1748). This alteration was detected in one control cohort individual; however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostCm	Uncertain	0.72
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D;.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.87
MVP		0.80
MPC		0.63
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.64
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 7
DS_DL_spliceai		0.86		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs36211723; hg19: chr11-47360071; COSMIC: COSV99920300;