NM_002474.3(MYH11):c.5499G>C (p.Glu1833Asp) AND not specified

Germline classification:: Likely benign (1 submission)
Last evaluated:: Jan 16, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000182531.15

Allele description [Variation Report for NM_002474.3(MYH11):c.5499G>C (p.Glu1833Asp)]

NM_002474.3(MYH11):c.5499G>C (p.Glu1833Asp)

Genes:

MYH11:myosin heavy chain 11 [Gene - OMIM - HGNC]
NDE1:nudE neurodevelopment protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.11

Genomic location:

Preferred name:

NM_002474.3(MYH11):c.5499G>C (p.Glu1833Asp)

Other names:

p.E1833D:GAG>GAC

HGVS:

NC_000016.10:g.15717145C>G
NG_009299.1:g.144886G>C
NG_021210.1:g.78879C>G
NM_001040113.2:c.5520G>C
NM_001040114.2:c.5520G>C
NM_001143979.1:c.948-7046C>G
NM_001143979.2:c.948-7046C>G
NM_002474.3:c.5499G>CMANE SELECT
NM_017668.3:c.948-7046C>GMANE SELECT
NM_022844.3:c.5499G>C
NP_001035202.1:p.Glu1840Asp
NP_001035203.1:p.Glu1840Asp
NP_001035203.1:p.Glu1840Asp
NP_002465.1:p.Glu1833Asp
NP_074035.1:p.Glu1833Asp
LRG_1401t1:c.5499G>C
LRG_1401t2:c.5520G>C
LRG_1401:g.144886G>C
LRG_1401p1:p.Glu1833Asp
LRG_1401p2:p.Glu1840Asp
NC_000016.9:g.15811002C>G
NM_001040113.1:c.5520G>C
NM_001040114.1:c.5520G>C
NM_002474.2:c.5499G>C

Protein change:

E1833D

Links:

dbSNP: rs145252402

NCBI 1000 Genomes Browser:

rs145252402

Molecular consequence:

NM_001143979.2:c.948-7046C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_017668.3:c.948-7046C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001040113.2:c.5520G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001040114.2:c.5520G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002474.3:c.5499G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_022844.3:c.5499G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001338027	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jan 16, 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

SCV001338027

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jan 16, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations.

Poninska JK, Bilinska ZT, Franaszczyk M, Michalak E, Rydzanicz M, Szpakowski E, Pollak A, Milanowska B, Truszkowska G, Chmielewski P, Sioma A, Janaszek-Sitkowska H, Klisiewicz A, Michalowska I, Makowiecka-Ciesla M, Kolsut P, Stawinski P, Foss-Nieradko B, Szperl M, Grzybowski J, Hoffman P, Januszewicz A, et al.

J Transl Med. 2016 May 4;14(1):115. doi: 10.1186/s12967-016-0870-4.

PubMed [citation]

PMID:: 27146836
PMCID:: PMC4855821

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338027.3

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

Description

Variant summary: MYH11 c.5520G>C (p.Glu1840Asp) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251074 control chromosomes, predominantly at a frequency of 0.00068 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 544 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5520G>C has been reported in the literature in an individual affected with bicuspid aortic valve and thoracic aortic aneurysm, however without evidence for causality (Poninska_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. At-least one co-occurrence with another pathogenic variant associated with Loeys-Dietz syndrome has been observed at our laboratory ( TGFB2 c.895C>T , p.Arg299Trp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=5; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Apr 15, 2024

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