NM_000256.3(MYBPC3):c.1219G>A (p.Gly407Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 23, 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:: RCV000156791.6

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1219G>A (p.Gly407Ser)]

NM_000256.3(MYBPC3):c.1219G>A (p.Gly407Ser)

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.1219G>A (p.Gly407Ser)

HGVS:

NC_000011.10:g.47343496C>T
NG_007667.1:g.14207G>A
NM_000256.3:c.1219G>AMANE SELECT
NP_000247.2:p.Gly407Ser
LRG_386t1:c.1219G>A
LRG_386:g.14207G>A
LRG_386p1:p.Gly407Ser
NC_000011.9:g.47365047C>T

Protein change:

G407S

Links:

dbSNP: rs727505266

NCBI 1000 Genomes Browser:

rs727505266

Molecular consequence:

NM_000256.3:c.1219G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000280206	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (Sep 1, 2014)	germline	clinical testing
SCV003934387	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 23, 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

SCV000280206

Stanford Center for Inherited Cardiovascular Disease, Stanford University

no assertion criteria provided

Uncertain significance
(Sep 1, 2014)

germline

clinical testing

SCV003934387

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 23, 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	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

Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure.

Waldmüller S, Erdmann J, Binner P, Gelbrich G, Pankuweit S, Geier C, Timmermann B, Haremza J, Perrot A, Scheer S, Wachter R, Schulze-Waltrup N, Dermintzoglou A, Schönberger J, Zeh W, Jurmann B, Brodherr T, Börgel J, Farr M, Milting H, Blankenfeldt W, Reinhardt R, et al.

Eur J Heart Fail. 2011 Nov;13(11):1185-92. doi: 10.1093/eurjhf/hfr074. Epub 2011 Jul 12.

PubMed [citation]

PMID:: 21750094

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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. p.Gly407Ser (c.1219 G>A) in MYBPC3 Based on the data reviewed below we consider this variant a variant of uncertain significance, likely disease causing. The variant has been seen in at least one unrelated cases of DCM with no segregation data. Waldmuller et al (2011) sequenced MYH7 and MYBPC3 in 652 patients with DCM from a multi-center German cohort and identified this variant in one patient. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glycine at codon 407 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (p.Ser408Asn, p.Gly416Ser). This substitution occurs 5 nucleotides from the end of exon 13, thus it is possible that the variant impacts splicing. I emailed GeneDx to ask what their in silico splicing prediction programs predict and they told me that the two algorithms they ran predict no impact on splicing. In total the variant has not been seen in ~6500 from publicly available population datasets. There is no variation at codon 407 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of March 8th, 2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of March 8 th, 2013).

#	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	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934387.1

#	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.1219G>A (p.Gly407Ser) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 210360 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1219G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Waldmuller_2011). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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: 21750094). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories 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 8, 2024

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