11-47351308-C-T

Variant names:

• chr11-47351308-C-T
• rs375471260
• NM_000256.3:c.223G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000256.3(MYBPC3):​c.223G>A​(p.Asp75Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,578,354 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. D75G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • 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: 7.38
• Publications: 16 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.223G>A	p.Asp75Asn	missense_variant	Exon 2 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.223G>A	p.Asp75Asn	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.223G>A	p.Asp75Asn	missense_variant	Exon 2 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.223G>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000152 AC: 3 AN: 197134 AF XY: 0.0000282

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000351

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000273 AC: 39 AN: 1425996 Hom.: 0 Cov.: 36 AF XY: 0.0000298 AC XY: 21 AN XY: 705752

African (AFR) AF: 0.00 AC: 0 AN: 32504

American (AMR) AF: 0.00 AC: 0 AN: 39686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25472

East Asian (EAS) AF: 0.0000534 AC: 2 AN: 37454

South Asian (SAS) AF: 0.00 AC: 0 AN: 81634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000293 AC: 32 AN: 1093650

Other (OTH) AF: 0.0000847 AC: 5 AN: 59042

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000453 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:3

Feb 09, 2017

Center for Human Genetics, University of Leuven

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG score unknown significance -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 75 of the MYBPC3 protein (p.Asp75Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 21488259, 21943931, 27600940, 28771489, 30871747, 31513939). ClinVar contains an entry for this variant (Variation ID: 161313). 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. 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. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 75 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 3 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 27600940, 31513939), as well as in a healthy control subject (PMID: 20433692). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has been identified in 4/228528 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. -

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

-

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jul 12, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp75Asn variant in MYBCP3 has been reported in 6 individuals with HCM and 1 individual with DCM (Rodriguez-Garcia 2010, Lakdawala 20111, Cecconi 2016, Mademont-Soler 2017, Walsh 2017, Wiffin 207, Sousa 2019). One individual with HCM carried an additional pathogenic variant in MYBPC3 (Mademont-Soler 2017). It has also been identified in 4/100946 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3. -

Cardiomyopathy Uncertain:1

Aug 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 75 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 8 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 27600940, 31513939, 32841044, 33495596, 33495597, 33782553), as well as in a healthy control individual (PMID: 20433692). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has been identified in 4/228528 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. -

not provided Uncertain:1

Jan 03, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with HCM, though many publications did not include patient-specific clinical details (Harris et al., 2011; Lakdawala et al., 2011; Andreasen et al., 2013; Amendola et al., 2015; Ho et al., 2015; Cecconi et al., 2016; Ito et al., 2017; Walsh et al., 2017); Reported in a 12-year-old Spanish female with HCM who also harbored a pathogenic MYBPC3 splice site variant (Mademont-Soler et al., 2017); Segregation studies in a family with HCM revealed this variant in one possibly affected family member and one family member with a normal phenotype, whereas the variant was absent in a family member with suggestive electrocardiographic alterations (Rodriguez-Garcia et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31513939, 30871747, 23299917, 25637381, 21488259, 27532257, 21943931, 28679633, 28771489, 27600940, 25543971, 21415409, 28518168) -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardiovascular phenotype Uncertain:1

Jun 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D75N variant (also known as c.223G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 223. The aspartic acid at codon 75 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts (Lopes LR et al. Heart, 2015 Feb;101:294-301; Rodr&iacute;guez-Garc&iacute;a MI et al. BMC Med Genet, 2010 Apr;11:67; Lakdawala NK et al. Am J Cardiol, 2011 Dec;108:1606-13; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Sousa A et al. Rev Port Cardiol (Engl Ed), 2019 Feb;38:129-139; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28). Functional studies suggest altered protein function; however, the physiological relevance of these findings is unclear (Kochurova AM et al. Int J Mol Sci, 2024 Oct;25: ; Nabiev SR et al. Int J Mol Sci, 2024 Dec;25:). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

MYBPC3-related disorder Uncertain:1

Oct 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYBPC3 c.223G>A variant is predicted to result in the amino acid substitution p.Asp75Asn. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Rodríguez-García et al. 2010. PubMed ID: 20433692; Supplemental Table in Lakdawala et al. 2011. PubMed ID: 21943931; Supplemental Table 2 in Mademont-Soler et al. 2017. PubMed ID: 28771489; Sousa et al. 2018. PubMed ID: 30871747; Supplemental Table 2 in Robyns et al. 2020. PubMed ID: 31513939). In one study, analysis of the proband's family, was not fully supportive for segregation (Rodríguez-García et al. 2010. PubMed ID: 20433692). This variant is reported in 0.0040% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47372859-C-T). In ClinVar, this variant has been interpreted as uncertain by the majority of submitting laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/161313/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
CardioboostCm	Benign	0.042
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.5	H;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MVP		0.92
MPC		0.82
ClinPred		0.91	D
GERP RS		4.3
Varity_R		0.75
gMVP		0.85
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs375471260; hg19: chr11-47372859;