rs730880610

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BP4_Strong

The NM_000256.3(MYBPC3):c.305C>T(p.Pro102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,501,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P102E?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 1.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47350602-GGG-GCCTC is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.029416144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.305C>T	p.Pro102Leu	missense_variant	3/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.305C>T	p.Pro102Leu	missense_variant	3/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.305C>T	p.Pro102Leu	missense_variant	3/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.305C>T		non_coding_transcript_exon_variant	3/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000187

AC:

AN:

107026

Hom.:

AF XY:

0.0000169

AC XY:

AN XY:

59050

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000211

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1349414

Hom.:

Cov.:

AF XY:

0.0000120

AC XY:

AN XY:

665766

show subpopulations

Gnomad4 AFR exome

AF:

0.000145

Gnomad4 AMR exome

AF:

0.0000516

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000375

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000612

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 probands, no segs -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2016	The P102L variant of uncertain significance has previously been reported in two unrelated Egyptian individuals with HCM and was absent from 200 ethnicity-matched control alleles (Kassem et al., 2013). This variant was reported as 'de novo' in both of these individuals; however, specific family history information or data on parental testing was not provided (Kaseem et al., 2013). The P102L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and Leucine is the wild type amino acid at this position in at least two species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Data from control individuals was not available to assess whether P102L may be a common benign variant in the general population. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 15, 2023	This missense variant replaces proline with leucine at codon 102 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 23233322; doi:10.25560/95088) as well as in several healthy individuals (doi:10.25560/95088). This variant has been identified in 2/107026 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	Jan 27, 2017	- -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 102 of the MYBPC3 protein (p.Pro102Leu). This variant is present in population databases (rs730880610, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23233322; Invitae). ClinVar contains an entry for this variant (Variation ID: 181030). 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	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces proline with leucine at codon 102 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 at least two individuals affected with hypertrophic cardiomyopathy (PMID: 23233322; doi:10.25560/95088) as well as in several healthy individuals (doi:10.25560/95088). This variant has been identified in 2/107026 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

Mendelics

May 28, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The p.P102L variant (also known as c.305C>T), located in coding exon 3 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 305. The proline at codon 102 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

CardioboostCm

Benign

0.010

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Uncertain

0.65

D;T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.022

D;D;D

Sift4G

Uncertain

0.051

T;D;D

Polyphen

0.0080

B;.;.

Vest4

0.71

MutPred

0.31

Loss of glycosylation at P102 (P = 0.031);Loss of glycosylation at P102 (P = 0.031);Loss of glycosylation at P102 (P = 0.031);

MVP

0.54

MPC

0.22

ClinPred

0.079

GERP RS

1.6

Varity_R

0.053

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over