NM_002474.3(MYH11):c.5887G>A (p.Ala1963Thr) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 13, 2024
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:: RCV001189159.5

Allele description [Variation Report for NM_002474.3(MYH11):c.5887G>A (p.Ala1963Thr)]

NM_002474.3(MYH11):c.5887G>A (p.Ala1963Thr)

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.5887G>A (p.Ala1963Thr)

HGVS:

NC_000016.10:g.15704023C>T
NG_009299.1:g.158008G>A
NG_021210.1:g.65757C>T
NM_001040113.2:c.*109G>A
NM_001040114.2:c.5908G>A
NM_001143979.2:c.947+7163C>T
NM_002474.3:c.5887G>AMANE SELECT
NM_017668.3:c.947+7163C>TMANE SELECT
NM_022844.3:c.*109G>A
NP_001035203.1:p.Ala1970Thr
NP_002465.1:p.Ala1963Thr
LRG_1401t1:c.5887G>A
LRG_1401t2:c.*109G>A
LRG_1401:g.158008G>A
LRG_1401p1:p.Ala1963Thr
NC_000016.9:g.15797880C>T
NM_001040113.1:c.*109G>A
NM_002474.2:c.5887G>A

Protein change:

A1963T

Links:

dbSNP: rs146413415

NCBI 1000 Genomes Browser:

rs146413415

Molecular consequence:

NM_001040113.2:c.*109G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_022844.3:c.*109G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001143979.2:c.947+7163C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_017668.3:c.947+7163C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001040114.2:c.5908G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002474.3:c.5887G>A - 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
SCV001356389	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 12, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002649491	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 13, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001356389

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 12, 2019)

germline

clinical testing

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

SCV002649491

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 13, 2024)

germline

clinical testing

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

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001356389.2

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

Description

This variant is located in the 3' untranslated region of the MYH11 protein. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282854 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, SCV002649491.2

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

Description

The p.A1963T variant (also known as c.5887G>A), located in coding exon 40 of the MYH11 gene, results from a G to A substitution at nucleotide position 5887. The alanine at codon 1963 is replaced by threonine, an amino acid with similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with thoracic aortic aneurysm and dissection (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear for autosomal dominant thoracic aortic aneurysm and dissection; however, it is unlikely to be causative of autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome.

#	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: Sep 1, 2024

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