rs138753870

Positions:

• chr11-47349779-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000256.3(MYBPC3):​c.649A>G​(p.Ser217Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,605,074 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:13
• Conservation: PhyloP100: 4.16

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 Benign. Variant got -7 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.009872884).
• BP6: Variant 11-47349779-T-C is Benign according to our data. Variant chr11-47349779-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=9}. Variant chr11-47349779-T-C is described in Lovd as [Pathogenic]. Variant chr11-47349779-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-47349779-T-C is described in Lovd as [Benign]. Variant chr11-47349779-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.649A>G	p.Ser217Gly	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.649A>G	p.Ser217Gly	missense_variant	5/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.649A>G	p.Ser217Gly	missense_variant	5/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.649A>G		non_coding_transcript_exon_variant	5/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152260 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00186 AC: 447 AN: 240264 Hom.: 4 AF XY: 0.00245 AC XY: 321 AN XY: 131232

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.000193

Gnomad NFE exome AF: 0.000907

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00109 AC: 1588 AN: 1452696 Hom.: 19 Cov.: 31 AF XY: 0.00145 AC XY: 1045 AN XY: 722992

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.000286

Gnomad4 NFE exome AF: 0.000485

Gnomad4 OTH exome AF: 0.000962

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152378 Hom.: 3 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74514

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000804 Hom.: 1

Bravo AF: 0.000786

ESP6500AA AF: 0.000482 AC: 2

ESP6500EA AF: 0.00119 AC: 10

ExAC AF: 0.00209 AC: 253

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MYBPC3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 01, 2016	reclassified based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	Reported in ClinVar as a benign and likely benign variant by other clinical laboratories (ClinVar Variant ID# 42780; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22763267, 19632136, 23299917, 22464770, 24503780, 25524337, 24119082, 22958901, 22361390, 21750094, 25351510, 26656175, 27650965, 27600940, 28416588, 29121657, 29032884) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Hypertrophic cardiomyopathy Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Pathogenic, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2015	p.Ser217Gly in exon 5 of MYBPC3: This variant is not expected to have clinical s ignificance because it has been identified in 1.2% (177/14558) of South Asian ch romosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs138753870). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2019	Variant summary: MYBPC3 c.649A>G (p.Ser217Gly) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 240264 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.649A>G has been reported in the literature in individuals affected with affected with hypertrophic- or dilated cardiomyopathy, however without strong evidence for causality (e.g. Roberts_2009, Millat_2010, Ogorodnikova_2011, Mestroni_2010, Lakdawala_2012, Merlo_2013, Pugh_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, Lakdawala_2012 reported that this variant did not segregate with the disease in one family. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.2827C>T (p.Arg943X) in an internal sample; MYH7 c.1357C>T, (p.Arg453Cys) in Roberts_2009), providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (5x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 23, 2017	- -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 04, 2018

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Left ventricular noncompaction 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 04, 2018

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 07, 2018

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: BS1, BS2, PP3 -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2016

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	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	0.018
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0099	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.066	T;T;T
Polyphen		0.91	P;.;.
Vest4		0.28
MVP		0.86
MPC		0.20
ClinPred		0.064	T
GERP RS		3.7
Varity_R		0.32
gMVP		0.67

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: rs138753870; hg19: chr11-47371330;