rs187705120

Positions:

• chr11-47332891-C-G
• chr11-47332891-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000256.3(MYBPC3):​c.3413G>C​(p.Arg1138Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,952 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. R1138C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:6
• Conservation: PhyloP100: 5.82

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47332891-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 11-47332891-C-G is Pathogenic according to our data. Variant chr11-47332891-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42712.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3413G>C	p.Arg1138Pro	missense_variant	31/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3413G>C	p.Arg1138Pro	missense_variant	31/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3413G>C	p.Arg1138Pro	missense_variant	30/34	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455952 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 723630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	Reported variant in the literature in individuals referred for cardiomyopathy testing, but clinical and segregation data are limited or absent (Coppini et al., 2014; Ito et al., 2017; Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25524337, 28679633, 27532257, 33297573) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2017	Variant summary: The MYBPC3 c.3413G>C (p.Arg1138Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 80556 control chromosomes and has been reported in the literature in at least one patient with HCM without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, until additional evidence becomes available, this variant is classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2018	- -

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 29, 2019	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2023	- -

Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2023

- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1138 of the MYBPC3 protein (p.Arg1138Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25524337, 27532257, 28679633; Invitae). ClinVar contains an entry for this variant (Variation ID: 42712). 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 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, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2013

The Arg1138Pro variant in MYBPC3 has not been reported in the literature nor pre viously identified by our laboratory. The frequency of this variant in large Eur opean American and African American populations cannot be determined from the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) because coverag e at this position was insufficient or unavailable. Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sug gest that this variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. At this time, additional information is needed to fully assess the clinical significance of this variant. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.3413G>C (p.R1138P) alteration is located in exon 31 (coding exon 31) of the MYBPC3 gene. This alteration results from a G to C substitution at nucleotide position 3413, causing the arginine (R) at amino acid position 1138 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.4	D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.97
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs187705120; hg19: chr11-47354442;