rs193922386

Positions:

• chr11-47346365-G-A
• chr11-47346365-G-C
• chr11-47346365-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000256.3(MYBPC3):​c.932C>T​(p.Ser311Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,432,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity MYPC3_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.13905641).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.932C>T	p.Ser311Leu	missense_variant	12/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.932C>T	p.Ser311Leu	missense_variant	12/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.932C>T	p.Ser311Leu	missense_variant	11/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.932C>T		non_coding_transcript_exon_variant	12/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000244 AC: 35 AN: 1432076 Hom.: 0 Cov.: 32 AF XY: 0.0000296 AC XY: 21 AN XY: 709184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000243

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000301

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 311 of the MYBPC3 protein (p.Ser311Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy, hypertrophic cardiomyopathy, or sudden unexplained death (PMID: 21750094, 27532257, 29247119). ClinVar contains an entry for this variant (Variation ID: 177928). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces serine with leucine at codon 311 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 25611685). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094). 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. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 23, 2023

This missense variant replaces serine with leucine at codon 311 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 25611685). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094). 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 4;C3715165:Left ventricular noncompaction 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 04, 2019

The p.Ser311Leu variant in MYBPC3 has been reported in 1 Caucasian individual with DCM (Waldmüller 2011) and has been identified by our laboratory in 1 Caucasian individual with RCM and in one affected relative. This variant was not identified in large population studies. Serine (Ser) at position 311 is not conserved in mammals or evolutionarily distant species and the change to leucine (Leu) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, 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

Oct 11, 2022

The p.S311L variant (also known as c.932C>T), located in coding exon 12 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 932. The serine at codon 311 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy cohort, a hypertrophic cardiomyopathy cohort, and a sudden unexplained death cohort; however, clinical details were limited in these cases (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:[ePub ahead of print]; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
CardioboostCm	Benign	0.00061
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.087	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.045	B;.;.
Vest4		0.73
MVP		0.70
MPC		0.19
ClinPred		0.33	T
GERP RS		4.4
Varity_R		0.078
gMVP		0.14

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: rs193922386; hg19: chr11-47367916; COSMIC: COSV57032766;