rs727504945

Variant names:

• chr11-47351247-A-G
• rs727504945
• NM_000256.3:c.284T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000256.3(MYBPC3):​c.284T>C​(p.Ile95Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,387,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I95L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.278
• Publications: 2 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.047510028).
• BP6: Variant 11-47351247-A-G is Benign according to our data. Variant chr11-47351247-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179554.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.284T>C	p.Ile95Thr	missense_variant	Exon 2 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.284T>C	p.Ile95Thr	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.284T>C	p.Ile95Thr	missense_variant	Exon 2 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.284T>C		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000594 AC: 1 AN: 168306 AF XY: 0.0000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000577 AC: 8 AN: 1387372 Hom.: 0 Cov.: 37 AF XY: 0.00000735 AC XY: 5 AN XY: 680386

African (AFR) AF: 0.00 AC: 0 AN: 31668

American (AMR) AF: 0.0000273 AC: 1 AN: 36586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24628

East Asian (EAS) AF: 0.00 AC: 0 AN: 35862

South Asian (SAS) AF: 0.00 AC: 0 AN: 78788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49606

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5498

European-Non Finnish (NFE) AF: 0.00000562 AC: 6 AN: 1067328

Other (OTH) AF: 0.00 AC: 0 AN: 57408

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Apr 17, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the MYBPC3 gene. The I95T variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I95T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and threonine (T) is the wild-type residue at this position in multiple mammalian species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, there are conflicting classifications in ClinVar where this variant is classified as both a variant of uncertain significance and a likely benign variant by other clinical laboratories (ClinVar SCV000206064.3, SCV000219630.2; Landrum et al., 2016). -

Hypertrophic cardiomyopathy Uncertain:1

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 95 of the MYBPC3 protein (p.Ile95Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179554). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified Benign:1

Apr 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile95Thr in exon 2 of MYBPC3: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, >10 mammals have a threonine (Thr) at this position despite high nearby amino acid conservation. In addition, this variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign p rediction is estimated to be correct 89% of the time (Jordan 2011). Ile95Thr in exon 2 of MYBPC3 (allele frequency = n/a) -

Cardiomyopathy Benign:1

Sep 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.0024
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.3
DANN	Benign	0.40
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PhyloP100		0.28
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.57	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.044
MutPred		0.37		Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);
MVP		0.14
MPC		0.28
ClinPred		0.048	T
GERP RS		-6.7
Varity_R		0.065
gMVP		0.23
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs727504945; hg19: chr11-47372798;