rs727503188

Positions:

• chr11-47337544-G-A
• chr11-47337544-G-C
• chr11-47337544-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3 PP5

The NM_000256.3(MYBPC3):​c.2449C>T​(p.Arg817Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,692 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R817G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 4.91

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 6 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, 10 uncertain in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337544-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 810770.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 11-47337544-G-A is Pathogenic according to our data. Variant chr11-47337544-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164078.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2449C>T	p.Arg817Trp	missense_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2449C>T	p.Arg817Trp	missense_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2449C>T	p.Arg817Trp	missense_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.2414-33C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249226 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135206

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 21, 2022	The MYBPC3 c.2449C>T variant is classified as VUS (PS4_Moderate, PM2, PP3) The MYBPC3 c.2449C>T variant is a single nucleotide change in exon 25/35 of the MYBPC3 gene, which is predicted to change the amino acid arginine at position 817 in the protein, to tryptophan. The variant has been reported in at least 6 probands with a clinical presentation of Hypertrophic cardiomyopathy (PS4_Moderate) (PMID#25351510, 28749478, 33782553). Other variants at this same amino acid have also been reported in individuals with HCM (p.Arg817Gln/Gly) (PMID#26914223, 3378553). This variant is absent from population databases (PM2), is reported in dbSNP (rs727503188), is reported as ?disease causing in HGMD (CM1516385) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar#164078). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has also been reported in a homozygous state in a foetus with hydrops fatalis. Parental testing was implied and indicated a 'lack of phenotype in carrier' however this was not confirmed with cardiac imaging (PubMed#28749478). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 05, 2024	- -

Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 05, 2024

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 817 of the MYBPC3 protein (p.Arg817Trp). 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 individuals with nonimmune hydrops fetalis and hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 28749478, 33782553, 36264615; Invitae). ClinVar contains an entry for this variant (Variation ID: 164078). 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. This variant disrupts the p.Arg817 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26914223, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 12, 2013

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2023

Identified in association with HCM in published literature (Lopes et al., 2015; Walsh et al., 2017; Thompson et al., 2021); Reported to be homozygous in at least one fetus with nonimmune hydrops fatalis (Shamseldin et al., 2018); Identified in a patient with HCM and status-post heart transplant who also harbored a second pathogenic variant in the MYBPC3 gene (Nafissi et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25351510, 26914223, 28679633, 34428338, 33782553, 27532257, 34645488, 34515413, 28749478, 36136372) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
CardioboostCm	Uncertain	0.70
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Pathogenic	4.0	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.2	D;.;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.81
MVP		0.91
MPC		0.85
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.79
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs727503188; hg19: chr11-47359095;