rs397515985

Positions:

• chr11-47335886-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000256.3(MYBPC3):​c.2728C>A​(p.Pro910Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,526,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:4
• Conservation: PhyloP100: 1.51

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_benign. Variant got -2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.028673232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2728C>A	p.Pro910Thr	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.2728C>A	p.Pro910Thr	missense_variant	26/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2728C>A	p.Pro910Thr	missense_variant	25/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*233C>A		non_coding_transcript_exon_variant	26/27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*233C>A		3_prime_UTR_variant	26/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152112 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000412

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000128 AC: 18 AN: 141174 Hom.: 0 AF XY: 0.000105 AC XY: 8 AN XY: 76210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000322

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 348 AN: 1373948 Hom.: 0 Cov.: 34 AF XY: 0.000220 AC XY: 149 AN XY: 676506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000603

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000413

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.000194

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152230 Hom.: 0 Cov.: 30 AF XY: 0.000202 AC XY: 15 AN XY: 74422

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.000232 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 19, 2024	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYBPC3: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2020	This variant is associated with the following publications: (PMID: 22361390, 21750094, 23861362, 18533079, 20215591, 21832052, 26914223, 27604170, 24111713, 21499742, 25351510, 21835320) -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Hypertrophic cardiomyopathy 4 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 02, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine (exon 26). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD v3 <0.001 for a dominant condition (29 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (Fibronectin type 3 domain; PDB, Decipher). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been previously regarded as likely benign and as a VUS (ClinVar, LOVD). In addition, it has been reported in individuals with HCM, dilated cardiomyopathy (DCM) and sudden death; however, in some cases this variant was identified in conjunction with other variants in relevant genes or known pathogenic variants in MYBPC3 gene. (PMID: 21832052, 24111713, 28840316). (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 07, 2023	This missense variant replaces proline with threonine at codon 910 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21835320, 24111713, 26914223), dilated cardiomyopathy (PMID: 20215591), sudden cardiac death (PMID: 21499742), and sudden infant death syndrome (PMID: 22361390). One individual with hypertrophic cardiomyopathy had a different pathogenic variant in the same gene (PMID: 21835320). This variant has been identified in 25/172572 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	Aug 12, 2021	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces proline with threonine at codon 910 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21835320, 24111713, 26914223), dilated cardiomyopathy (PMID: 20215591), sudden cardiac death (PMID: 21499742), and sudden infant death syndrome (PMID: 22361390). One individual with hypertrophic cardiomyopathy had a different pathogenic variant in the same gene (PMID: 21835320). This variant has been identified in 25/172572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary 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	Jan 22, 2024	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 910 of the MYBPC3 protein (p.Pro910Thr). This variant is present in population databases (rs397515985, 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 MYBPC3-related conditions (PMID: 20215591, 21499742, 21835320, 22361390, 24111713, 25351510, 26914223). ClinVar contains an entry for this variant (Variation ID: 42656). 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. 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. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2024	Variant summary: MYBPC3 c.2728C>A (p.Pro910Thr) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 141174 control chromosomes, predominantly at a frequency of 0.00032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05). c.2728C>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Pinto_2011), Hypertrophic cardiomyopathy (Olivotto_2008), and syncopal episodes with family history of sudden cardiac death (Allegue_2011). A recent large cohort of cross-sectional study based on UK biobank and gnomAD samples reported a similar distribution of this variant in the HCM cohort and controls (allele frequency of 0.00028 in HCM vs. 0.00023 in controls) with a penetrance of 0.002 (McGurk_2023). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in protein stability by measuing melting temperature in E. coli (Suay-Corredera_2021). The following publications have been ascertained in the context of this evaluation (PMID: 21499742, 37652022, 21835320, 21832052, 34097875). ClinVar contains an entry for this variant (Variation ID: 42656). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 10, 2017	proposed classification - variant undergoing re-assessment, contact laboratory -

Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Conduction disorder of the heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jan 03, 2020

- -

Brugada syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 01, 2014

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
CardioboostCm	Benign	0.0018
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.066	T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.39	N;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.57	N;.;N
REVEL	Benign	0.26
Sift	Benign	0.44	T;.;T
Sift4G	Benign	0.41	T;T;T
Vest4		0.13
MVP		0.61
MPC		0.26
ClinPred		0.020	T
GERP RS		0.49
Varity_R		0.086
gMVP		0.39

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: rs397515985; hg19: chr11-47357437;