NM_002474.3(MYH11):c.4345A>C (p.Lys1449Gln) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 18, 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:: RCV000771986.7

Allele description [Variation Report for NM_002474.3(MYH11):c.4345A>C (p.Lys1449Gln)]

NM_002474.3(MYH11):c.4345A>C (p.Lys1449Gln)

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.4345A>C (p.Lys1449Gln)

HGVS:

NC_000016.10:g.15724181T>G
NG_009299.1:g.137850A>C
NG_021210.1:g.85915T>G
NM_001040113.2:c.4366A>C
NM_001040114.2:c.4366A>C
NM_001143979.2:c.948-10T>G
NM_002474.2:c.4345A>C
NM_002474.3:c.4345A>CMANE SELECT
NM_017668.3:c.948-10T>GMANE SELECT
NM_022844.3:c.4345A>C
NP_001035202.1:p.Lys1456Gln
NP_001035203.1:p.Lys1456Gln
NP_002465.1:p.Lys1449Gln
NP_074035.1:p.Lys1449Gln
LRG_1401t1:c.4345A>C
LRG_1401t2:c.4366A>C
LRG_1401:g.137850A>C
LRG_1401p1:p.Lys1449Gln
LRG_1401p2:p.Lys1456Gln
NC_000016.9:g.15818038T>G
NM_001040113.1:c.4366A>C
NM_001040113.2:c.4366A>C
NM_001143979.1:c.948-10T>G

Protein change:

K1449Q

Links:

dbSNP: rs775809843

NCBI 1000 Genomes Browser:

rs775809843

Molecular consequence:

NM_001143979.2:c.948-10T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_017668.3:c.948-10T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001040113.2:c.4366A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001040114.2:c.4366A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002474.3:c.4345A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_022844.3:c.4345A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000904941	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004087818	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 18, 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

SCV000904941

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 16, 2022)

germline

clinical testing

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

SCV004087818

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 18, 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Congenital ductus arteriosus aneurysm in association with MYH11 mutation: a case report.

Ardhanari M, Swaminathan S.

Cardiol Young. 2020 Jan;30(1):123-125. doi: 10.1017/S1047951119003287. Epub 2020 Jan 9.

PubMed [citation]

PMID:: 31916526

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000904941.4

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

Description

This missense variant replaces lysine with glutamine at codon 1456 of the MYH11 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 14/277236 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV004087818.2

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

Description

The p.K1449Q variant (also known as c.4345A>C), located in coding exon 30 of the MYH11 gene, results from an A to C substitution at nucleotide position 4345. The lysine at codon 1449 is replaced by glutamine, an amino acid with similar properties. This variant (referred to as NM_001040113.1c.4366A>C, p. Lys1456Gln) has been detected in a case with congenital ductus arteriosus aneurysm and intestinal atresia (Ardhanari M et al. Cardiol Young, 2020 Jan;30:123-125). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 1, 2024

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