NM_000256.3(MYBPC3):c.1786G>A (p.Gly596Arg) AND Hypertrophic cardiomyopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001083913.8

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1786G>A (p.Gly596Arg)]

NM_000256.3(MYBPC3):c.1786G>A (p.Gly596Arg)

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.1786G>A (p.Gly596Arg)

Other names:

p.G596R:GGG>AGG

HGVS:

NC_000011.10:g.47341995C>T
NG_007667.1:g.15708G>A
NM_000256.3:c.1786G>AMANE SELECT
NP_000247.2:p.Gly596Arg
LRG_386t1:c.1786G>A
LRG_386:g.15708G>A
LRG_386p1:p.Gly596Arg
NC_000011.9:g.47363546C>T
c.1786G>A

Protein change:

G596R

Links:

dbSNP: rs199728019

NCBI 1000 Genomes Browser:

rs199728019

Molecular consequence:

NM_000256.3:c.1786G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence

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
SCV000259413	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004842443	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 7, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21511876, 25351510, 25558701, 27930701, 32746448, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000259413

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 31, 2024)

germline

clinical testing

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

SCV004842443

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 7, 2023)

germline

clinical testing

PubMed (6)
[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	31	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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Sarcomere protein gene mutations in patients with apical hypertrophic cardiomyopathy.

Gruner C, Care M, Siminovitch K, Moravsky G, Wigle ED, Woo A, Rakowski H.

Circ Cardiovasc Genet. 2011 Jun;4(3):288-95. doi: 10.1161/CIRCGENETICS.110.958835. Epub 2011 Apr 21.

PubMed [citation]

PMID:: 21511876

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000259413.9

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

#	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, SCV004842443.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	31	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has also been identified in 21/203560 chromosomes (14/9070 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary 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		31	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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