rs727503206

Variant names:

• chr11-47343108-T-G
• rs727503206
• NM_000256.3:c.1264A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000256.3(MYBPC3):​c.1264A>C​(p.Thr422Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,744 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

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 domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 21 pathogenic changes around while only 3 benign (88%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1264A>C	p.Thr422Pro	missense_variant	Exon 15 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1264A>C	p.Thr422Pro	missense_variant	Exon 15 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1264A>C	p.Thr422Pro	missense_variant	Exon 14 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1264A>C		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459744 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726010

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Thr422Pro variant in MYBPC3 has not been reported in individuals with cardio myopathy and data from large population studies is insufficient to assess the fr equency of this variant. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to ful ly assess the clinical significance of the Thr422Pro variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
CardioboostCm	Uncertain	0.16
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.6	D;.;D
REVEL	Pathogenic	0.79
Sift	Benign	0.077	T;.;T
Sift4G	Uncertain	0.028	D;D;D
Vest4		0.77
MVP		0.93
MPC		0.93
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs727503206; hg19: chr11-47364659;