rs730880702

chr11-47332173-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3713T>C(p.Leu1238Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1238L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.94

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 16 ACMG points.

• PM1: In a domain Ig-like C2-type 7 (size 93) in uniprot entity MYPC3_HUMAN there are 46 pathogenic changes around while only 3 benign (94%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 11-47332173-A-G is Pathogenic according to our data. Variant chr11-47332173-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332173-A-G is described in Lovd as [Pathogenic]. Variant chr11-47332173-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3713T>C	p.Leu1238Pro	missense_variant	33/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3713T>C	p.Leu1238Pro	missense_variant	33/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3713T>C	p.Leu1238Pro	missense_variant	32/34	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 26, 2017	Testing was performed at GeneDx. Given the moderate case data, segregation at least 4 individuals in one family, and absence in population databases, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Pursuing additional segregation studies in other affected family members could strengthen the segregation data for this variant. The variant has been seen in at least 4 unrelated individuals with HCM (not including this patient's family). There is mild segregation data from the one family reported in the literature. A different genetic testing laboratory noted that they have seen this variant in one individual with HCM. Choi et al. 2010 report a Korean family in which 4 individuals with HCM carry this variant. Below is a pedigree for reference. Of note, the paper does not indicate how these patients were tested for genetic variants and do not list which genes were included in the original genetic testing. II-3 was 63yo at last follow up had an IVSd measuring 2.9cm, had NSVT on Holter and has an ICD. He had an EF of 70% and MRI showed areas of delayed enhancement. III-2 has HCM dx at age 40 with an IVSd 2.3cm, EF of 30%, apical thrombus, LAE, and afib. She also had hypertension. III-3 has HCM dx at age 27 with history of afib and VT, IVSd measuring 2.4cm and EF of 25%. Authors note he progressed to heart failure and DCM-like phenotype. He died of intractable VT at age 54. III-5 has HCM dx at age 28 with improved EF on follow up. IVSd of 1.7cm, NSVT on Holter and EF of 39%. Authors note he was a heavy alcoholic and developed a DCM phenotype at age 31. Once he gave up alcohol his EF and LVEDD returned to normal. Berge et al (2014) reports this variant in a Norwegian proband with HCM. No specific phenotypic information is included. Genetic testing was done on a research basis and not at a known laboratory, to our knowledge. Walsh et al (2016), in collaboration with Cook, Ware, and MacArthur, report that is variant was identified in an individual with HCM. Testing was performed at Oxford Medical Genetics Laboratories. No other details are provided. The variant is not present in the SHaRe database. There is no variation at codon 1238 listed in the Exome Aggregation Consortium Dataset (ExAC; http://exac.broadinstitute.org/), which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is 70x. There is no variation at codon 1238 listed in the Genome Aggregation Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 80x for exomes and 35x for genomes. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2017	The L1238P variant in the MYBPC3 gene has been reported in two probands with HCM (Choi et al., 2010; Berge et al., 2014). The variant segregated with HCM in 5 relatives of one affected proband (Choi et al., 2010). The L1238P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L1238P variant is a semiconservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181136, PMID:20641121, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96, 3CNET: 0.996, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1238 of the MYBPC3 protein (p.Leu1238Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20641121, 24111713, 27532257, 32841044, 35653365; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181136). 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 disruptive. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 32841044). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The p.L1238P variant (also known as c.3713T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3713. The leucine at codon 1238 is replaced by proline, an amino acid with similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and has been noted to segregate with disease (Choi JO et al. Clin Cardiol, 2010 Jul;33:430-8; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Wright CF et al. Am J Hum Genet, 2019 Feb;104:275-286; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.4	D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.98
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0

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: rs730880702; hg19: chr11-47353724;