11-47343496-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000256.3(MYBPC3):c.1219G>A(p.Gly407Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000566 in 1,589,498 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G407R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.38

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 3 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 25 pathogenic changes around while only 8 benign (76%) in NM_000256.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1219G>A	p.Gly407Ser	missense_variant	13/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1219G>A	p.Gly407Ser	missense_variant	13/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1219G>A	p.Gly407Ser	missense_variant	12/34	5		A2
MYBPC3	ENST00000544791.1	c.1219G>A	p.Gly407Ser	missense_variant, NMD_transcript_variant	13/27	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000487 AC: 7 AN: 1437384 Hom.: 0 Cov.: 51 AF XY: 0.00000421 AC XY: 3 AN XY: 712586

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: 0.00000636

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 01, 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. p.Gly407Ser (c.1219 G>A) in MYBPC3 Based on the data reviewed below we consider this variant a variant of uncertain significance, likely disease causing. The variant has been seen in at least one unrelated cases of DCM with no segregation data. Waldmuller et al (2011) sequenced MYH7 and MYBPC3 in 652 patients with DCM from a multi-center German cohort and identified this variant in one patient. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glycine at codon 407 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (p.Ser408Asn, p.Gly416Ser). This substitution occurs 5 nucleotides from the end of exon 13, thus it is possible that the variant impacts splicing. I emailed GeneDx to ask what their in silico splicing prediction programs predict and they told me that the two algorithms they ran predict no impact on splicing. In total the variant has not been seen in ~6500 from publicly available population datasets. There is no variation at codon 407 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of March 8th, 2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of March 8 th, 2013). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2023	Variant summary: MYBPC3 c.1219G>A (p.Gly407Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 210360 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1219G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Waldmuller_2011). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21750094). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	The p.Gly407Ser variant in MYBPC3 has been reported in 1 German individual with DCM (Waldmuller 2011). It was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Gly407Ser variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 407 of the MYBPC3 protein (p.Gly407Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 21750094). ClinVar contains an entry for this variant (Variation ID: 179988). 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. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The p.G407S variant (also known as c.1219G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1219. The glycine at codon 407 is replaced by serine, an amino acid with similar properties. This variant has been detected in a dilated cardiomyopathy cohort; however, details were limited (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92). This amino acid position is highly 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. -

MYBPC3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2023

The MYBPC3 c.1219G>A variant is predicted to result in the amino acid substitution p.Gly407Ser. This variant was reported in one individual with dilated cardiomyopathy; however, further clinical details were not provided (Supplementary Table 2, Waldmüller et al 2011. PubMed ID: 21750094). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, other variants at the same amino acid (p.Gly407Arg and p.Gly407Asp) have been reported in patients with MYBPC3-related disease (Coban-Akdemir et al. 2020. PubMed ID: 32233023; Supplementary Table 1, Wang et al. 2014. PubMed ID: 25132132). Although we suspect that the c.1219G>A (p.Gly407Ser) variant could be pathogenic, at this time, we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Benign	0.046
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	0.042
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.012	D;T;T
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.80	P;.;.
Vest4		0.84
MutPred		0.23		Gain of disorder (P = 0.0624);Gain of disorder (P = 0.0624);Gain of disorder (P = 0.0624);
MVP		0.86
MPC		0.81
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.60

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: rs727505266; hg19: chr11-47365047;