rs370890951

chr11-47332912-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000256.3(MYBPC3):c.3392T>C(p.Ile1131Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000869 in 1,610,014 control chromosomes in the GnomAD database, including 1 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 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 7.14

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020005107).
• BP6: Variant 11-47332912-A-G is Benign according to our data. Variant chr11-47332912-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42711.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=1}. Variant chr11-47332912-A-G is described in Lovd as [Likely_pathogenic]. Variant chr11-47332912-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3392T>C	p.Ile1131Thr	missense_variant	31/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3392T>C	p.Ile1131Thr	missense_variant	31/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3392T>C	p.Ile1131Thr	missense_variant	30/34	5		A2

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000804 AC: 194 AN: 241172 Hom.: 0 AF XY: 0.000802 AC XY: 105 AN XY: 130886

Gnomad AFR exome AF: 0.000207

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000887 AC: 1293 AN: 1457866 Hom.: 1 Cov.: 34 AF XY: 0.000876 AC XY: 635 AN XY: 724786

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00307

Gnomad4 NFE exome AF: 0.000984

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000794 AC XY: 59 AN XY: 74342

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000739 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000744 AC: 3

ESP6500EA AF: 0.000482 AC: 4

ExAC AF: 0.000827 AC: 100

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	Reported in ClinVar as a likely benign / benign variant (ClinVar Variant ID 42711; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22361390, 22958901, 16352453, 24510615, 23054336, 15519027, 23140321, 23299917, 20624503, 14563344, 23785128, 25163546, 24503780, 26633542) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 27, 2015	p.Ile1131Thr in exon 31 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 0.3% (14/4490) of Finnish chromo somes and 0.15% (72/48504) of European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370890951). Additionally, isoleucine (Ile) at position 1131 is not conserved in mammals or evolutionarily distant species and 1 mammal (prairie vole) carries a threonine (Thr) at this po sition, supporting that this change may be tolerated. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2021	Variant summary: MYBPC3 c.3392T>C (p.Ile1131Thr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 272528 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.0 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 Non-Finnish European origin. c.3392T>C has been reported in the literature as a non-informative finding in hypertrophic cardiomyopathy cohorts (example, Alders_2003, Mook_2013, VanDriest_2004, Salazar-Mendiguchia_2020), dilated cardiomyopathy cohorts (example, Haas_2015), SIDS cohorts undergoing multigene panel testing (example, Brion_2012) and within the ESP cohort (Andreasen_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least two reports of a co-occurrence with another pathogenic variant have been reported (MYBPC3 c.2373dupG, p.Trp792fsX41, Alders_2003, Mook_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority concordance as likely benign (n=7)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2018	- -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 12, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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

Mar 12, 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. -

Cardiac arrest Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 04, 2014

- -

Left ventricular noncompaction Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2019

This alteration is classified as likely 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	0.33
CardioboostCm	Benign	0.0033
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Vest4		0.37
MVP		0.87
MPC		0.28
ClinPred		0.063	T
GERP RS		5.3
Varity_R		0.30
gMVP		0.18

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: rs370890951; hg19: chr11-47354463; COSMIC: COSV57032510; COSMIC: COSV57032510;