rs181834806

chr11-47342658-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000256.3(MYBPC3):c.1544A>G(p.Asn515Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N515N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 5.78

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_benign. Variant got -1 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 51 pathogenic changes around while only 13 benign (80%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.10034549).
• BP6: Variant 11-47342658-T-C is Benign according to our data. Variant chr11-47342658-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36602.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=7, Benign=2}. Variant chr11-47342658-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1544A>G	p.Asn515Ser	missense_variant	17/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1544A>G	p.Asn515Ser	missense_variant	17/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1544A>G	p.Asn515Ser	missense_variant	16/34	5		A2
MYBPC3	ENST00000544791.1	c.1544A>G	p.Asn515Ser	missense_variant, NMD_transcript_variant	17/27	5

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000963 AC: 24 AN: 249256 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135216

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461696 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727134

Gnomad4 AFR exome AF: 0.00203

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74494

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.000692 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2012	The Asn515Ser variant in MYBPC3 has been identified in 3/4338 African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs181834806). This frequency is too low to rul e out a role in disease. Our laboratory has detected this variant in 3 individua ls (1 adult individual with HCM and 2 individuals with early onset HCM or HCM + additional congenital heart defects). Of these, 2 individuals were of Black ance stry, which is consistent with the above results by the NHLBI Exome Sequencing P roject (see above). Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. However, asparagine (Asn) at position 515 is highly conserved across evolutionarily distant species, increasing the likeliho od that an amino acid change would not be tolerated. In summary, additional info rmation is needed to fully assess the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2021	Variant summary: MYBPC3 c.1544A>G (p.Asn515Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consistently, a recent study evaluating the impact of this variant on protein destabilization as estimated by a software that estimates changes in free energy upon mutation from emperically and statistically derived energy functions (FoldX), reported a non-pathogenic outcome (Suay-Corredara_2021). The variant allele was found at a frequency of 0.0001 in 250110 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1544A>G has been reported in the literature in individuals who did not meet the diagnostic criteria for Hypertrophic Cardiomyopathy (example Bick_2012) and as a VUS in settings of multigene panel testing in cohorts of patients with dilated cardiomyopathy (DCM) (example, Verdonschot_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Left ventricular noncompaction 10 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 21, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2019	This variant is associated with the following publications: (PMID: 22763267, 22958901, 24510615, 32880476) -

Hypertrophic cardiomyopathy 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 21, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2021

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.021
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.29	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.95	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	N;.;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;.;T
Sift4G	Benign	0.18	T;T;T
Vest4		0.80
MVP		0.82
MPC		0.33
ClinPred		0.055	T
GERP RS		4.6
Varity_R		0.17
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs181834806; hg19: chr11-47364209;