rs371564200

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000256.3(MYBPC3):​c.1828G>T​(p.Asp610Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,836 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. D610H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

16
3
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.48
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000256.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-47341207-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42576.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=9}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.1828G>T p.Asp610Tyr missense_variant 19/35 ENST00000545968.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.1828G>T p.Asp610Tyr missense_variant 19/355 NM_000256.3 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.1828G>T p.Asp610Tyr missense_variant 18/345 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.1828G>T p.Asp610Tyr missense_variant, NMD_transcript_variant 19/275

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1446836
Hom.:
0
Cov.:
35
AF XY:
0.00000139
AC XY:
1
AN XY:
718234
show subpopulations
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:
9.05e-7
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 07, 2021This missense variant replaces aspartic acid with tyrosine at codon 610 of the MYBPC3 protein. Computational prediction suggests that this variant may have 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 11, 2021This variant disrupts the p.Asp610amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 25740977, 28356264, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYBPC3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 610 of the MYBPC3 protein (p.Asp610Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
CardioboostCm
Uncertain
0.25
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;T;T
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
3.8
H;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-7.8
D;.;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;.;D
Sift4G
Pathogenic
0.0
D;D;D
Vest4
0.97
MVP
0.96
MPC
0.92
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.93
gMVP
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47362758; API