NM_000256.3(MYBPC3):c.2783C>T (p.Ser928Leu) AND Hypertrophic cardiomyopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000799722.6

Allele description

NM_000256.3(MYBPC3):c.2783C>T (p.Ser928Leu)

Gene:

MYBPC3:myosin binding protein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.2783C>T (p.Ser928Leu)

HGVS:

NC_000011.10:g.47335164G>A
NG_007667.1:g.22539C>T
NM_000256.3:c.2783C>TMANE SELECT
NP_000247.2:p.Ser928Leu
LRG_386t1:c.2783C>T
LRG_386:g.22539C>T
LRG_386p1:p.Ser928Leu
NC_000011.9:g.47356715G>A
p.(Ser928Leu)

Protein change:

S928L

Links:

dbSNP: rs773819168

NCBI 1000 Genomes Browser:

rs773819168

Molecular consequence:

NM_000256.3:c.2783C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000939398	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 23, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16335287, 22857948, 24111713, 33782553, 28492532
SCV004836715	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22857948, 24111713, 31323898, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000939398

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 23, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004836715

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Malignant mutations in hypertrophic cardiomyopathy: fact or fancy?

Brito D, Madeira H.

Rev Port Cardiol. 2005 Sep;24(9):1137-46. Review. English, Portuguese.

PubMed [citation]

PMID:: 16335287

Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.

Thompson AD, Helms AS, Kannan A, Yob J, Lakdawala NK, Wittekind SG, Pereira AC, Jacoby DL, Colan SD, Ashley EA, Saberi S, Ware JS, Ingles J, Semsarian C, Michels M, Mazzarotto F, Olivotto I, Ho CY, Day SM.

Genet Med. 2021 Jul;23(7):1281-1287. doi: 10.1038/s41436-021-01134-9. Epub 2021 Mar 29.

PubMed [citation]

PMID:: 33782553
PMCID:: PMC8257482

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000939398.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 928 of the MYBPC3 protein (p.Ser928Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16335287, 22857948, 24111713, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 427958). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004836715.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces serine with leucine at codon 928 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: 24111713, 22857948, 31323898). One of these individuals also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 22857948). This variant has been identified in 6/247572 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		6	not provided	not provided	not provided

Last Updated: May 1, 2024

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