rs730880595

Positions:

• chr11-47332609-C-A
• chr11-47332609-C-G
• chr11-47332609-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000256.3(MYBPC3):​c.3584G>T​(p.Gly1195Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.47

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 9 ACMG points.

• PM1: In a domain Ig-like C2-type 7 (size 93) in uniprot entity MYPC3_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 11-47332609-C-A is Pathogenic according to our data. Variant chr11-47332609-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181013.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	Protein	UniProt
MYBPC3	NM_000256.3	c.3584G>T	p.Gly1195Val	missense_variant	32/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3584G>T	p.Gly1195Val	missense_variant	32/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.3584G>T	p.Gly1195Val	missense_variant	31/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2014

p.Gly1195Val (GGC>GTC): c.3584 G>T in exon 32 of the MYBPC3 gene (NM_000256.3). The G1195V variant in the MYBPC3 gene has been reported in two patients with HCM and was not reported in at least 400 control alleles (Santos D et al., 2012; Brito D et al., 2012). The G1195V variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, this substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (L1187R, V1192D, A1194T, L1200P) have been reported in association with HCM, supporting the functional importance of this region of the protein. However, the G1195V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with HCM, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (DCM) (CirinoAet al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s). -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Sep 24, 2014

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly1195Val Based on the information reviewed below, we classify it as a variant of unknown significance (VUS). Although this is a good candidate for a pathogenic mutation, the possibility that it is a benign variant cannot be excluded at this time. This variant has been previously reported twice in association with hypertrophic cardiomyopathy, but it is not clear if this is actually 2 reports on the same Portuguese individual. No segregation analysis is available. Santos et al. (2012, BMC Med Genet) reported this as a novel variant in one 25-year-old Portuguese male diagnosed with sporadic obstructive HCM (no family history). He also carried a p.Leu44Pro variant in CSRP3. Authors apparently from the same group (Brito et al 2012) reported it as a novel variant in one Portuguese individual with HCM and a history of sudden cardiac death in a first-degree relative. No further relatives were available for study. This is a conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a nonpolar Valine. Glycine at this location is completely conserved across vertebrate species sequenced. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. In silico analysis predicts the variant to be probably damaging to protein structure/function. Nearby variants, within 10 amino acids to either side, have also been reported in HGMD in association with hypertrophic cardiomyopathy or LVNC: Leu1187Arg, Val1192Asp, Ala1194Thr, Leu1200Pro (as of January 2014). In total the variant has not been seen in 6200 controls and individuals from publicly available population datasets. (Our patient has African-American ancestry.) Santos et al. (2012) and Brito et al. (2012) did not detect it in 100 healthy Portuguese control individuals. This variant is not present in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on 4100 Caucasian and 2000 African-American individuals (as of July 22, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. No variation at this codon is present in 1000 Genomes (http://browser.1000genomes.org) or dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2020

The p.G1195V variant (also known as c.3584G>T), located in coding exon 32 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3584. The glycine at codon 1195 is replaced by valine, an amino acid with dissimilar properties. This variant was detected in individuals with a personal or family history of hypertrophic cardiomyopathy (Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Santos S et al. BMC Med. Genet., 2012 Mar;13:17). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.97
CardioboostCm	Uncertain	0.86
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.3	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.0	D;.;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.95
MVP		0.98
MPC		0.93
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.96

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: rs730880595; hg19: chr11-47354160;