rs397515972

Variant names:

• chr11-47337456-ACGCGCATCT-A
• rs397515972
• NM_000256.3:c.2528_2536delAGATGCGCG

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2528_2536delAGATGCGCG​(p.Glu843_Arg845del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E843E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYBPC3 NM_000256.3 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000256.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-47337456-ACGCGCATCT-A is Pathogenic according to our data. Variant chr11-47337456-ACGCGCATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337456-ACGCGCATCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	disruptive_inframe_deletion	Exon 25 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	disruptive_inframe_deletion	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	disruptive_inframe_deletion	Exon 24 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*33_*41delAGATGCGCG		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*33_*41delAGATGCGCG		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Feb 21, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu843_Arg845del variant (MYBPC3) has not been reported in the literature no r previously identified in > 3300 probands (>2000 Caucasian) tested by our labor atory. This low frequency supports a pathogenic role. This variant is predicted to cause an in-frame deletion removing a lysine (Lys), methionine (M), and argin ine (Arg) from positions 843-845. These three amino acids are all highly conserv ed in mammals and evolutionarily distant species, and the loss of multiple conse rved amino acids is likely to have a severe effect on the protein. In summary, d ue to the rarity of the variant and the severity of the change, the Glu843_Arg84 5del variant is likely to be pathogenic. -

Cardiovascular phenotype Pathogenic:1

Aug 16, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_mod, PM2, PM4 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515972; hg19: chr11-47359007;