rs371401403

Positions:

• chr11-47335996-G-A
• chr11-47335996-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_000256.3(MYBPC3):​c.2618C>T​(p.Pro873Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,528,322 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P873H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:10
• Conservation: PhyloP100: 9.58

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 domain Fibronectin type-III 2 (size 95) in uniprot entity MYPC3_HUMAN there are 23 pathogenic changes around while only 7 benign (77%) in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47335996-G-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2618C>T	p.Pro873Leu	missense_variant	26/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2618C>T	p.Pro873Leu	missense_variant	26/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2618C>T	p.Pro873Leu	missense_variant	25/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*123C>T		non_coding_transcript_exon_variant	26/27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*123C>T		3_prime_UTR_variant	26/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152136 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000680 AC: 12 AN: 176378 Hom.: 0 AF XY: 0.0000736 AC XY: 7 AN XY: 95100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000293

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: 0.0000363

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000269 AC: 37 AN: 1376068 Hom.: 0 Cov.: 34 AF XY: 0.0000281 AC XY: 19 AN XY: 676476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000343

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: 0.0000197

Gnomad4 OTH exome AF: 0.0000705

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152254 Hom.: 0 Cov.: 30 AF XY: 0.0000403 AC XY: 3 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000680

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 30, 2024	This missense variant replaces proline with leucine at codon 873 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported an individual affected with hypertrophic cardiomyopathy (PMID: 27600940) and in an individual affected with isolated left ventricular non-compaction cardiomyopathy (PMID: 21551322). It has also been reported in two individuals affected with dilated cardiomyopathy as well as in one healthy relative (PMID: 27173948, 32826072). This variant has been identified in 13/207756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 15, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 873 of the MYBPC3 protein (p.Pro873Leu). This variant is present in population databases (rs371401403, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with left ventricular noncompaction or dilated cardiomyopathy (PMID: 21551322, 27173948). ClinVar contains an entry for this variant (Variation ID: 64615). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2023	Variant summary: MYBPC3 c.2618C>T (p.Pro873Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 176378 control chromosomes (gnomAD). The observed variant frequency is approximately two fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.2618C>T has been reported in the literature in individuals affected with left ventricular noncompaction cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy (Probst_2011, Haas_2014, Reinstein_2016, Cecconi_2016, Lin_2021). These data indicate that the variant may 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: 27066506, 27600940, 25163546, 34819141, 23861362, 21551322, 27173948). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2015	This mutation is denoted p.Pro873Leu (aka P873L) at the protein level and c.2618 C>T at the cDNA level. The Pro873Leu mutation in the MYBPC3 gene has been published previously in association with cardiomyopathy (Probst, 2011). Pro873Leu was reported in a 37 year old male patient with decompensated congestive heart failure, and was not present in 360 control chromosomes (Probst, 2011). Another mutation affecting the same residue (Pro873His) has also been reported in association with HCM (Probst, 2011), further supporting the functional importance of this region of the protein.The variant is found in HCM panel(s). -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	This missense variant replaces proline with leucine at codon 873 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported an individual affected with hypertrophic cardiomyopathy (PMID: 27600940) and in an individual affected with isolated left ventricular non-compaction cardiomyopathy (PMID: 21551322). It has also been reported in two individuals affected with dilated cardiomyopathy as well as in one healthy relative (PMID: 27173948, 32826072). This variant has been identified in 13/207756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -

Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2011

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 22, 2021

- -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The p.P873L variant (also known as c.2618C>T), located in coding exon 26 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2618. The proline at codon 873 is replaced by leucine, an amino acid with similar properties. This variant has been detected in a patient with left ventricular noncompaction and heart failure (Probst S et al. Circ Cardiovasc Genet, 2011 Aug;4:367-74). This variant has also been reported in an individual with dilated cardiomyopathy, developmental delay and hearing loss who also had a variant in the CASK gene; however, four relatives with MYBPC3 p.P873L had normal echocardiograms (Reinstein E et al. Genet Res (Camb). 2016 05;98:e8). Additionally, this alteration was detected as a secondary cardiac variant in an exome cohort in an individual without known cardiomyopathy (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.1	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.021	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.97
MVP		0.96
MPC		0.84
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs371401403; hg19: chr11-47357547;