11-47346207-C-T

Position:

• chr11-47346207-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1090G>A​(p.Ala364Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• 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:7
• Conservation: PhyloP100: 4.66

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 12 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 21 pathogenic changes around while only 3 benign (88%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47346207-C-T is Pathogenic according to our data. Variant chr11-47346207-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346207-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1090G>A	p.Ala364Thr	missense_variant, splice_region_variant	12/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1090G>A	p.Ala364Thr	missense_variant, splice_region_variant	12/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1090G>A	p.Ala364Thr	missense_variant, splice_region_variant	11/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1090G>A		splice_region_variant, non_coding_transcript_exon_variant	12/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 27, 2023	This variant changes the last nucleotide c.G of exon 12 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 12 splice donor site. RNA studies from a carrier individual have shown that this variant causes an out-of-frame skipping of exon 12 (PMID: 30645170, 33530161). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 7 individuals affected with hypertrophic cardiomyopathy (PMID: 20513729, 20800588, 21239446, 21302287, 25740977, 30645170, 32481709, 32841044, 35208637; SCV000924849.1), and in one individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has not been identified 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 25, 2021	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant changes the last nucleotide c.G of exon 12 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 12 splice donor site. RNA studies from a carrier individual have shown that this variant causes an out-of-frame skipping of exon 12 (PMID: 30645170, 33530161). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 7 individuals affected with hypertrophic cardiomyopathy (PMID: 20513729, 20800588, 21239446, 21302287, 25740977, 30645170, 32481709, 32841044, 35208637; SCV000924849.1), and in one individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has not been identified 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 364 of the MYBPC3 protein (p.Ala364Thr). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20513729, 21239446, 21302287, 25740977). ClinVar contains an entry for this variant (Variation ID: 454301). 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. 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. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Apr 25, 2017

Testing for our patient was performed at Invitae. Given the moderate case data, possible effect on splicing, and absence in general population databases, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 7 unrelated cases of HCM, one of which is a patient at our center. There is moderate case data. All of the cases are of Italian descent. Roncarati et al (2011) saw this variant in 1 patient with HCM and noted there may be a potential effect on splicing. Patient was recruited in Italy, but not in Padua. Calore et al. (2015) reports this variant in 5 index cases of HCM from a cohort in Padua, Italy. The variant has also been reported in other papers from overlapping groups in Italy (Fokstuen 2011; Melacini 2010), but these cases are not counted in the overall case count given possible redundancy of patients. The paper by Roncarati et al. also cites Smaniotto et al. (2009), but I was unable to find the actual paper. Even so, the authors were Italian and any cases reported in that paper could be overlapping. Per the lab report, algorithms predict that this variant could have an effect on splicing. Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). Many MYBPC3 splice variants have been reported in association with HCM including IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). Another variant at the same codon Ala364Pro, which is considered a VUS by a reputable laboratory. That variant is absent from gnomAD. The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD genomes is 51x and in gnomAD exomes is 32x. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2024

The c.1090G>A variant (also known as p.A364T), located in coding exon 12 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1090. The threonine at codon 364 is replaced by alanine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 12 and may have some effect on normal mRNA splicing. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Melacini P et al. Eur. Heart J., 2010 Sep;31:2111-23; Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91; Fokstuen S et al. J. Med. Genet., 2011 Aug;48:572-6; Roncarati R et al. J. Cell. Physiol., 2011 Nov;226:2894-900; Calore C et al. J. Med. Genet., 2015 May;52:338-47). RNA and minigene studies indicate that this alteration results in abnormal splicing (Crehalet H et al. Cardiogenetics, 2012; v.2:e6; Singer ES et al. Circ Genom Precis Med. 2019 Jan;12(1):e002368). Both the nucleotide and amino acid positions are well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

MYBPC3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The MYBPC3 c.1090G>A variant is predicted to result in the amino acid substitution p.Ala364Thr. This variant is located at the last nucleotide of exon 12 and is predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant was reported in numerous individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (Melacini et al. 2010. PubMed ID: 20513729; Millat et al. 2010. PubMed ID: 20800588; Roncarati et al. 2011. PubMed ID: 21302287; Calore et al. 2015. PubMed ID: 25740977; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221; Table S1, Preveden et al. 2022. PubMed ID: 35208637). mRNA studies using affected individual's blood sample showed that this variant results in the skipping of exon 12 and a subsequent frameshift (Figure S1F, Singer et al. 2019. PubMed ID: 30645170). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.017
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.92	P;.;.
Vest4		0.76
MutPred		0.34		Gain of phosphorylation at A364 (P = 0.027);Gain of phosphorylation at A364 (P = 0.027);Gain of phosphorylation at A364 (P = 0.027);
MVP		0.86
MPC		0.33
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		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: rs794727046; hg19: chr11-47367758;