rs199893357

chr11-47338618-G-Achr11-47338618-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000256.3(MYBPC3):c.2210C>T(p.Thr737Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T737T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 3.09

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 1 ACMG points.

• PM1: In a strand (size 4) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.3763353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2210C>T	p.Thr737Met	missense_variant	23/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2210C>T	p.Thr737Met	missense_variant	23/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2210C>T	p.Thr737Met	missense_variant	22/34	5		A2
MYBPC3	ENST00000544791.1	c.2210C>T	p.Thr737Met	missense_variant, NMD_transcript_variant	23/27	5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000603 AC: 15 AN: 248960 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135128

Gnomad AFR exome AF: 0.0000646

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: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 121 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74334

Gnomad4 AFR AF: 0.000145

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: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.0000496 AC: 6

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	Reported in association with HCM and DCM; however, this variant is also observed in individuals with no known history of cardiomyopathy (Walsh et al., 2017; Mazzarotto et al., 2020; Bick et al., 2012; Ng et al., 2013; Thompson et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 23861362, 21310275, 31983221, 32746448, 27532257, 33782553) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 10, 2022	BP4 -

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 31, 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.Thr737Met in MYBPC3 The p.Thr737Met variant is novel. The c.2210C>T substitution was identified in exon 23 of MYBPC3, resulting in a non-conservative amino acid substitution of a polar neutral threonine with non-polar neutral methionine. The threonine residue is conserved across other mammalian species. In silico analysis with PolyPhen2 predicts the variant to be probably damaging. A variant has been reported in association with HCM at a nearby codon (p.Arg733Cys, Van Driest et al 2004). In total the variant has not been seen in ~4 of ~7,134 laboratory controls and individuals from publicly available population datasets. The variant was recently reported online in 2 of 4197 Caucasian individuals and 0 of 2077 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of April 9th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, other variants with strong evidence for pathogenicity have been seen in this dataset at a similar frequency, so this does not necessarily mean that the variant is not pathogenic. The variant is also listed in dbSNP (rs199893357) with note that it was observed in 2 of ~560 individuals in the NHGRI ClinSeq cohort. 1000 genomes lists the variant, but only in reference to the dbSNP entry. The p.Thr737Met variant was not detected in up to 300 individuals of Caucasian and African American ancestry tested at GeneDx. The pathogenicity of this novel variant is currently uncertain. It may contribute to the patient’s cardiomyopathy or it may be a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2011	The Thr737Met variant in MYBPC3 has not been reported in the literature though i t has been identified in 1 individual with HCM out of >1900 Caucasian probands ( 3800 chromosomes) tested by our laboratory. This low frequency is consistent wit h a pathogenic role. However, threonine (Thr) at position 737 is not completely conserved in evolution, suggesting that a change may be tolerated. Furthermore, this variant was predicted to be benign using a novel computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well -established clinical significance. This tool's benign interpretation is estimat ed to be correct 89% of the time, which suggests but does not prove that this va riant is benign (Jordan 2011). In summary, the clinical significance of this var iant cannot be determined without additional studies. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2023	This missense variant replaces threonine with methionine at codon 737 of the MYBPC3 protein. Computational prediction suggests that this variant may have a neutral impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 31983221 and 32746448). This variant has also been identified in 21/280356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 31, 2021	- -

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 737 of the MYBPC3 protein (p.Thr737Met). This variant is present in population databases (rs199893357, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of MYBPC3-related conditions (PMID: 27532257, 31983221, 32746448, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 42608). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces threonine with methionine at codon 737 of the MYBPC3 protein. Computational prediction suggests that this variant may have a neutral impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 31983221 and 32746448). This variant has also been identified in 21/280356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2021

The c.2210C>T (p.T737M) alteration is located in exon 23 (coding exon 23) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2210, causing the threonine (T) at amino acid position 737 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Left ventricular noncompaction 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
CardioboostCm	Benign	0.0030
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.86	D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.017	D;.;D
Sift4G	Uncertain	0.025	D;D;D
Vest4		0.35
MVP		0.94
MPC		0.36
ClinPred		0.15	T
GERP RS		4.4
Varity_R		0.035
gMVP		0.55

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: rs199893357; hg19: chr11-47360169;