NM_000256.3(MYBPC3):c.1505G>A (p.Arg502Gln) AND not provided

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Sep 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:: RCV000158097.34

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1505G>A (p.Arg502Gln)]

NM_000256.3(MYBPC3):c.1505G>A (p.Arg502Gln)

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.1505G>A (p.Arg502Gln)

Other names:

p.R502Q:CGG>CAG

HGVS:

NC_000011.10:g.47342697C>T
NG_007667.1:g.15006G>A
NM_000256.3:c.1505G>AMANE SELECT
NP_000247.2:p.Arg502Gln
LRG_386t1:c.1505G>A
LRG_386:g.15006G>A
LRG_386p1:p.Arg502Gln
NC_000011.9:g.47364248C>T
Q14896:p.Arg502Gln
c.1505G>A
p.(Arg502Gln)

Protein change:

R502Q

Links:

UniProtKB: Q14896#VAR_027881; dbSNP: rs397515907

NCBI 1000 Genomes Browser:

rs397515907

Molecular consequence:

NM_000256.3:c.1505G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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RecName: Full=G-protein coupled receptor 182; AltName: Full=G10D; AltName: Full=...
RecName: Full=G-protein coupled receptor 182; AltName: Full=G10D; AltName: Full=NOW
gi|1169785|sp|P43142.1|GP182_MOUSE

Protein
9,000 years of genetic continuity at Oakhurst rockshelter, South Africa
9,000 years of genetic continuity at Oakhurst rockshelter, South Africa
9,000 years of genetic continuity at Oakhurst rockshelter, South Africa

BioProject
PREDICTED: popeye domain-containing protein 3 [Capra hircus]
PREDICTED: popeye domain-containing protein 3 [Capra hircus]
gi|1062882559|ref|XP_017908608.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208032	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 1, 2023)	germline	clinical testing	Citation Link,
SCV000280215	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Apr 22, 2013)	germline	clinical testing
SCV000809463	Gharavi Laboratory, Columbia University	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000927183	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Feb 28, 2017)	germline	clinical testing	Citation Link,
SCV001446594	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001502063	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2020)	germline	clinical testing	Citation Link,
SCV002501534	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2021)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 9562578, 31589614, 12106841, 33407484, 22386539, 29907873, 21310275, 31918855, 31006259, 30847666, 27532257, 31447099, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing, research
not provided	germline	not provided	9	not provided	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

Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.

Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE.

N Engl J Med. 1998 Apr 30;338(18):1248-57.

PubMed [citation]

PMID:: 9562578

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.

Capalbo A, Valero RA, Jimenez-Almazan J, Pardo PM, Fabiani M, Jiménez D, Simon C, Rodriguez JM.

PLoS Genet. 2019 Oct;15(10):e1008409. doi: 10.1371/journal.pgen.1008409.

PubMed [citation]

PMID:: 31589614
PMCID:: PMC6797235

See all PubMed Citations (13)

Details of each submission

From GeneDx, SCV000208032.13

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20298698, 15115610, 20378854, 32952175, 34097875, 34060810, 16715312, 31918855, 27532257, 18803133, 25342278, 22386539, 27600940, 26507537, 26183555, 25892673, 18957093, 22857948, 24093860, 24510615, 20433692, 22112859, 18403758, 16566405, 16858239, 18533079, 17224687, 22267749, 30645170, 29687901, 20738943, 29907873, 28166811, 21310275, 28193612, 31006259, 31447099, 30847666, 33658040, 9562578, 31589614, 12106841, 33407484, 34400558, 35208637, 36243179, 36264615, 36252119, 36136372, 35653365, 12707239)

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280215.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg502Gln Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 9 unrelated cases of HCM with moderately strong segregation data in two different families. Niimura et al (1998) first reported the variant in two families with HCM. The variant segregated with disease in 4 members of one family and 5 members of the other, with the furthest degree of relationship between affecteds with the variant in each family being 2nd degree. Cardim et al (2005) observed the variant in a Portugese patient with HCM. Rudzinski et al (2008) observed the variant in one Polish HCM patient. Girolami et al (2006) observed the variant in two unrelated patients with HCM (likely the same two families in Olivotto et al 2008). Morita et al (2008) observed p.Arg502Gln in a child with HCM. A German group observed the variant in one patient with HCM (Ehlermann et al 2008). This may be the same case reported in a methods paper by Zeller et al (2006). Rodriguez-Garcia et al (2010) observed the variant in two unrelated Spanish families with HCM and in one of those families there were two affected individuals with the variant. The arginine at codon 502 is highly conserved. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Another variant (p.Arg502Trp) at the same codon, which we consider very likely disease causing, was recently reported as the most common HCM-causing variant with a frequency of 2.4% in HCM patients (Saltzman et al 2010). Variants in nearby codons have also been reported in association with HCM (p.Arg495Gln, p.Lys505del, p.Gly507Arg). In total the variant has not been seen in ~418 published controls: 100 (Niimura et al 1998), 118 (Rudzinski et al 2008), 200 (Rodriguez-Garcia et al 2010). p.Arg502Gln is not listed in the NHLBI Exome Sequencing Project dataset, however, p.Arg502Trp was observed in 1 of 3472 Caucasians and 0 of 1826 Caucasians in that dataset (as of 1/16/2012). Individual phenotypes from that dataset are not available. Several different cohorts from studies on common complex cardiovascular disease were pooled to create that sample. There is no variant at codon 502 listed in dbSNP or 1000 genomes (as of 1/16/2012).

#	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		9	not provided	not provided	not provided

From Gharavi Laboratory, Columbia University, SCV000809463.1

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

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

From Blueprint Genetics, SCV000927183.1

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

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446594.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001502063.22

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

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

From AiLife Diagnostics, AiLife Diagnostics, SCV002501534.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

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

Last Updated: Oct 13, 2024

Relating variation to medicine