11-47342616-G-C

Position:

• chr11-47342616-G-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.1586C>G​(p.Thr529Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,230 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: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.52

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 3 (size 90) in uniprot entity MYPC3_HUMAN there are 33 pathogenic changes around while only 9 benign (79%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1586C>G	p.Thr529Ser	missense_variant	17/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1586C>G	p.Thr529Ser	missense_variant	17/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1586C>G	p.Thr529Ser	missense_variant	16/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1586C>G		non_coding_transcript_exon_variant	17/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461230 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726878

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2011

Variant classified as Uncertain Significance - Favor Pathogenic. The Thr529Ser v ariant has not been reported in the literature, and has been identified by our l aboratory in individual with HCM (this individual?s son) out of >2,000 Caucasian probands. Threonine (Thr) at position 529 is highly conserved across several ev olutionary distant species, increasing the likelihood that the change is pathoge nic. In addition, computational tools (AlignGVGD, Polyphen2, SIFT) predict this change to be deleterious, though the accuracy of these tools is unknown. Additio nal data is needed to further classify the clinical significance of the Thr529Se r variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
CardioboostCm	Benign	0.073
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0090	D;D;D
Vest4		0.91
MVP		0.92
MPC		0.63
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.23
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515911; hg19: chr11-47364167;