rs373056282

Positions:

• chr11-47335065-G-A

Variant summary

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

The NM_000256.3(MYBPC3):​c.2882C>T​(p.Pro961Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000538 in 1,578,686 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 6.28

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 domain Fibronectin type-III 2 (size 95) in uniprot entity MYPC3_HUMAN there are 23 pathogenic changes around while only 7 benign (77%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.31761366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2882C>T	p.Pro961Leu	missense_variant	27/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2882C>T	p.Pro961Leu	missense_variant	27/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2882C>T	p.Pro961Leu	missense_variant	26/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000530 AC: 12 AN: 226206 Hom.: 0 AF XY: 0.0000569 AC XY: 7 AN XY: 122932

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000498 AC: 71 AN: 1426362 Hom.: 0 Cov.: 31 AF XY: 0.0000496 AC XY: 35 AN XY: 705672

Gnomad4 AFR exome AF: 0.000185

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000307

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000330

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2023	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: 20800588, 23299917, 25637381, 27532257, 12403824, 19858127, 33297573, 20031618, 34486814, 26582918) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 06, 2017	The p.Pro961Leu variant (rs373056282) was reported by Kaski et al. (2009) in one individual with mild concentric LV hypertrophy in a cohort of patients with early onset HCM. Using a wide pool of participants from NHLBI Exome Sequencing Project many previously disease associated variants, including p.Pro961Leu, were classified as uncertain significance (Andreasen et al. 2013 and Amendola et al. 2015). This is further confirmed by Walsh et al. (2017) classification of p.Pro961Leu as uncertain significance, given the overall population frequency of 0.005 percent (identified on 5 out of 103876 chromosomes) from the Exome Aggregation Consortium. The proline at position 961 is highly conserved and computational analyses of the effects of the p.Pro961Leu variant on protein structure and function is conflicting (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro961Leu variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 05, 2021	PM2 -

Hypertrophic cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces proline with leucine at codon 961 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20031618, 27532257, 33297573). This variant has been identified in 13/257588 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 961 of the MYBPC3 protein (p.Pro961Leu). This variant is present in population databases (rs373056282, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031618, 27532257, 33297573). ClinVar contains an entry for this variant (Variation ID: 42665). 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 leucine 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	The p.Pro961Leu variant in MYBPC3 has been reported in 2 individuals with HCM (Kaski 2009, Millat 2010), and has been identified by our laboratory in two African American individuals with HCM, one of whom carried a pathogenic variant in MYH7. This variant has also been identified in 1/8550 African and 3/9792 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373056282). Proline (Pro) at position 961 is not conserved in evolution and 3 mammals (chinchilla, brush-tailed rat, and platypus) carry a leucine (Leu), supporting that this change may be tolerated. In summary, due to the presence of conflicting data, the clinical significance of the p.Pro961Leu variant is uncertain. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2023	This missense variant replaces proline with leucine at codon 961 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20031618, 27532257, 33297573). This variant has been identified in 13/257588 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. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 29, 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.Pro961Leu (c.2882C>T) in MYBPC3 Given the type of variant, the co-occurrence with other pathogenic variants, and the uncertain phenotype of several of the individuals with the variant, we consider this variant a variant of uncertain significance and do not feel it is appropriate for predictive genetic testing. It is possible the variant may behave as a modifier. The variant has been seen in at least 3 unrelated cases of HCM, at least 2 of 3 had another pathogenic variant (not including this patient's family). It has also been seen in someone with left ventricular hypertrophy and a family history of sudden death and HCM. The variant has also been seen in multiple people not selected for HCM. Kaski et al (2009) observed the variant in one ""non-white"" patient with mild, concentric left ventricular hypertrophy, identified after the sudden death of his sibling with autopsy diagnosis of HCM. DNA was not available on sister to check for the variant. Father carried the variant and had normal echo but abnormal ECG. No other family history of medical history is provided. The authors note that 5 subjects had multiple variants but they don’t specific which subjects or variants. Millat et al (2010) reported the variant in a validation study of a high resolution melting technique for identification of variants in HCM patients. The patients came from their French cohort. Bick et al (2012) observed the variant in two individuals in the Jackson Heart Study, who were not selected for HCM. Left ventricular wall thickness was available on one of them, 0.9 cm. LMM has a ClinVar entry, SCV000059186, with an assertion of variant of uncertain significance. They note that they have seen the variant in two Black individuals with HCM and both had another variant classified as pathogenic or likely pathogenic. UW Medical Genetics has a ClinVar entry as well, SCV000190397, with an assertion of variant of uncertain significance. No specific data was shared and it was noted this was observed in research. Bick et al (2012) observed the variant in two individuals in the Jackson Heart Study. left ventricular wall thickness was available on one of them, 0.9 cm. In the supplemental data it specifies that the variant of interest (MYBPC3 p.Pro961Leu (c.2882C>T)) was found in one individual, age 42, who had one physical risk factor that was examined in this study. These risk factors included hyperlipidemia, hypertension, obesity, or diabetes. No other information was provided for this individual. The second subject identified to carry this variant was age 53 and had the following cardiac phenotype: LV wall thickness 0.9cm, LV diastolic diameter 4.93cm, L atrial diameter 3.6cm, fractional shortening 0.28, no risk factors. Note these individuals may overlap with the data from ExAC, reviewed below. Other variants have been reported in association with disease at nearby codons (p.Thr957Ser, p.Thr958Ile, p.Arg970Gln (per lab report summary of HGMD data)). The variant was reported online in 5 of 52,333 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 2016). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012)." -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2020

The c.2882C>T (p.P961L) alteration is located in exon 27 (coding exon 27) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2882, causing the proline (P) at amino acid position 961 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Mar 09, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
CardioboostCm	Benign	0.0018
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.2	D;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;D
Sift4G	Benign	0.064	T;T;T
Vest4		0.35
MVP		0.87
MPC		0.25
ClinPred		0.57	D
GERP RS		4.2
Varity_R		0.39
gMVP		0.73

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: rs373056282; hg19: chr11-47356616;