rs397516062

Positions:

• chr11-47349792-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.636C>G​(p.Ser212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,374 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 1.00

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 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.636C>G	p.Ser212Arg	missense_variant	5/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.636C>G	p.Ser212Arg	missense_variant	5/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.636C>G	p.Ser212Arg	missense_variant	5/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.636C>G	p.Ser212Arg	missense_variant, NMD_transcript_variant	5/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455374 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724238

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.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico splicing algorithms predict this variant results in the creation of a cryptic splice donor site upstream of the natural splice donor site for intron 5; This variant is associated with the following publications: (PMID: 18533079, 27532257, 33782553, 28679633) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2015	- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 212 of the MYBPC3 protein (p.Ser212Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 27532257, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 42776). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28679633). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 18, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser212Arg variant in MYBPC3 has been reported in 1 individual with HCM (Olivotto 2008) an d was absent from large population studies. It has also been identified by our l aboratory in 2 Caucasian adults with HCM and segregated with the disease in 2 af fected relatives. Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. The change to arginine (Arg) at position 212 was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is es timated to be correct 89% of the time (Jordan 2011). However, this variant is pr edicted to create an alternative 5' splice site, and while this is not predictiv e enough to determine pathogenicity, it is consistent with the established mecha nism of disease for MYBPC3. In summary, though its clinical significance remains uncertain, its presence in multiple affected individuals, segregation with dise ase, and possible splicing impact raise suspicion that this variant may have a r ole in disease. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2022

The c.636C>G (p.S212R) alteration is located in exon 5 (coding exon 5) of the MYBPC3 gene. This alteration results from a C to G substitution at nucleotide position 636, causing the serine (S) at amino acid position 212 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
CardioboostCm	Benign	0.036
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.085	T;T;T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.93	P;.;.
Vest4		0.85
MutPred		0.95		Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);Loss of disorder (P = 0.0883);
MVP		0.89
MPC		0.72
ClinPred		0.80	D
GERP RS		3.9
Varity_R		0.30
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516062; hg19: chr11-47371343;