NM_000256.3(MYBPC3):c.667G>A (p.Glu223Lys) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 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:: RCV000225898.7

Allele description [Variation Report for NM_000256.3(MYBPC3):c.667G>A (p.Glu223Lys)]

NM_000256.3(MYBPC3):c.667G>A (p.Glu223Lys)

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.667G>A (p.Glu223Lys)

HGVS:

NC_000011.10:g.47348529C>T
NG_007667.1:g.9174G>A
NM_000256.3:c.667G>AMANE SELECT
NP_000247.2:p.Glu223Lys
LRG_386t1:c.667G>A
LRG_386:g.9174G>A
LRG_386p1:p.Glu223Lys
NC_000011.9:g.47370080C>T
c.667G>A

Protein change:

E223K

Links:

dbSNP: rs397516069

NCBI 1000 Genomes Browser:

rs397516069

Molecular consequence:

NM_000256.3:c.667G>A - 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

Recent activity

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Homo sapiens polypyrimidine tract binding protein 2 (PTBP2), transcript variant ...
Homo sapiens polypyrimidine tract binding protein 2 (PTBP2), transcript variant 3, mRNA
gi|1677499936|ref|NM_001300987.2|

Nucleotide
sulfoquinovosyl transferase SQD2 isoform X2 [Glycine max]
sulfoquinovosyl transferase SQD2 isoform X2 [Glycine max]
gi|955331144|ref|XP_014633489.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000284251	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28771489, 28492532
SCV004834740	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28771489, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000284251

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 3, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004834740

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (2)
[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	4	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.

Mademont-Soler I, Mates J, Yotti R, Espinosa MA, Pérez-Serra A, Fernandez-Avila AI, Coll M, Méndez I, Iglesias A, Del Olmo B, Riuró H, Cuenca S, Allegue C, Campuzano O, Picó F, Ferrer-Costa C, Álvarez P, Castillo S, Garcia-Pavia P, Gonzalez-Lopez E, Padron-Barthe L, Díaz de Bustamante A, et al.

PLoS One. 2017;12(8):e0181465. doi: 10.1371/journal.pone.0181465.

PubMed [citation]

PMID:: 28771489
PMCID:: PMC5542623

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000284251.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 42785). This missense change has been observed to co-occur in individuals with a different variant in MYBPC3 that has been determined to be pathogenic (PMID: 28771489), but the significance of this finding is unclear. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28771489). This variant is present in population databases (rs397516069, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 223 of the MYBPC3 protein (p.Glu223Lys).

#	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, SCV004834740.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glutamic acid with lysine at codon 223 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with hypertrophic cardiomyopathy, who also carried a pathogenic truncation variant in the same gene that could explain the observed phenotype (PMID: 28771489). This variant has been identified in 23/245622 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		4	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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