NM_000256.3(MYBPC3):c.667G>A (p.Glu223Lys) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 12, 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:: RCV000035661.7

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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tRNA (cytosine(38)-C(5))-methyltransferase isoform g [Homo sapiens]
tRNA (cytosine(38)-C(5))-methyltransferase isoform g [Homo sapiens]
gi|1005261142|ref|NP_001307936.1|

Protein
Arabidopsis thaliana Receptor-like protein kinase-related family protein (AT1G63...
Arabidopsis thaliana Receptor-like protein kinase-related family protein (AT1G63580), mRNA
gi|1063690922|ref|NM_105036.2|

Nucleotide
daa27h04.x1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4057590 3', mRNA seque...
daa27h04.x1 NICHD_XGC_Lu1 Xenopus laevis cDNA clone IMAGE:4057590 3', mRNA sequence
gi|12747598|gnl|dbEST|7838320|gb|BG 2.1|

Nucleotide
Nucleic Acid Synthesis Inhibitors [Pharmacological Action]
Nucleic Acid Synthesis Inhibitors [Pharmacological Action]

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059312	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004122783	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059312

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 30, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004122783

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 12, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059312.5

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

Description

The p.Glu223Lys variant in MYBPC3 has been identified by our laboratory in 1 adu lt with HCM who also carried a pathogenic MYBPC3 variant on the other allele (in trans). This variant has been identified in 0.1% (11/8852) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs397516069). Computational prediction tools and conservation analysis sugges t that the p.Glu223Lys variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical sig nificance of the p.Glu223Lys variant is uncertain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122783.1

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

Description

Variant summary: MYBPC3 c.667G>A (p.Glu223Lys) results in a conservative amino acid change located in the Immunoglobulin subtype (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 245622 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (9.4e-05 vs 0.001), allowing no conclusion about variant significance. c.667G>A has been reported in the literature in an individual affected with Cardiomyopathy (Mademont-Soler_2017), also carrying a pathogenic variant (MYBPC3 c.2190del, p.K731Rfs*23), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28771489). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Oct 26, 2024

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