rs1555121660

chr11-47339739-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000256.3(MYBPC3):c.1979T>C(p.Val660Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V660M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr11-47339740-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180960.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1979T>C	p.Val660Ala	missense_variant	21/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1979T>C	p.Val660Ala	missense_variant	21/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1979T>C	p.Val660Ala	missense_variant	20/34	5		A2
MYBPC3	ENST00000544791.1	c.1979T>C	p.Val660Ala	missense_variant, NMD_transcript_variant	21/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 454308). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 660 of the MYBPC3 protein (p.Val660Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
CardioboostCm	Benign	0.0069
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;D;N
REVEL	Benign	0.22
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Vest4		0.56
MVP		0.91
MPC		0.56
ClinPred		0.90	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs1555121660; hg19: chr11-47361290;