rs727504318

Variant names:

• chr11-47350503-T-C
• rs727504318
• NM_000256.3:c.405A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000256.3(MYBPC3):​c.405A>G​(p.Lys135Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,404,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.690
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 11-47350503-T-C is Benign according to our data. Variant chr11-47350503-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177780.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.405A>G	p.Lys135Lys	splice_region synonymous	Exon 3 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.405A>G	p.Lys135Lys	splice_region synonymous	Exon 3 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.405A>G	p.Lys135Lys	splice_region synonymous	Exon 3 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.405A>G		splice_region non_coding_transcript_exon	Exon 3 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000303 AC: 5 AN: 165108 AF XY: 0.0000335

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: 0.0000702

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1404666 Hom.: 0 Cov.: 31 AF XY: 0.0000230 AC XY: 16 AN XY: 694970

African (AFR) AF: 0.00 AC: 0 AN: 31288

American (AMR) AF: 0.00 AC: 0 AN: 33496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24748

East Asian (EAS) AF: 0.00 AC: 0 AN: 36652

South Asian (SAS) AF: 0.00 AC: 0 AN: 79162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5166

European-Non Finnish (NFE) AF: 0.0000230 AC: 25 AN: 1085898

Other (OTH) AF: 0.00 AC: 0 AN: 58132

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Lys135Lys varia nt (MYBPC3) has not been reported in the literature but has been identified in o ne individual with HCM by our laboratory. This variant is located in the last t hree bases of the exon, which is part of the 5? splice region. Computational too ls do not predict a strong effect on splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, this variant is less li kely pathogenic but additional information is needed to fully assess its clinica l significance.

Hypertrophic cardiomyopathy Uncertain:1

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 135 of the MYBPC3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs727504318, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 28679633). ClinVar contains an entry for this variant (Variation ID: 177780). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Cardiovascular phenotype Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.405A>G variant (also known as p.K135K), located in coding exon 3 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 405. This nucleotide substitution does not change the lysine at codon 135. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405; Westphal DS et al. J Cardiovasc Dev Dis, 2022 Jan;9:[ePub ahead of print]). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the available evidence, the clinical significance of this variant remains unclear.

Cardiomyopathy Benign:1

Oct 25, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		0.69
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504318; hg19: chr11-47372054;