NM_002474.3(MYH11):c.5406C>G (p.His1802Gln) AND Aortic aneurysm, familial thoracic 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 7, 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:: RCV000641576.14

Allele description [Variation Report for NM_002474.3(MYH11):c.5406C>G (p.His1802Gln)]

NM_002474.3(MYH11):c.5406C>G (p.His1802Gln)

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.5406C>G (p.His1802Gln)

HGVS:

NC_000016.10:g.15717238G>C
NG_009299.1:g.144793C>G
NG_021210.1:g.78972G>C
NM_001040113.2:c.5427C>G
NM_001040114.2:c.5427C>G
NM_001143979.2:c.948-6953G>C
NM_002474.3:c.5406C>GMANE SELECT
NM_017668.3:c.948-6953G>CMANE SELECT
NM_022844.3:c.5406C>G
NP_001035202.1:p.His1809Gln
NP_001035203.1:p.His1809Gln
NP_002465.1:p.His1802Gln
NP_074035.1:p.His1802Gln
LRG_1401t1:c.5406C>G
LRG_1401t2:c.5427C>G
LRG_1401:g.144793C>G
LRG_1401p1:p.His1802Gln
LRG_1401p2:p.His1809Gln
NC_000016.9:g.15811095G>C
NM_001040113.1:c.5427C>G
NM_001143979.1:c.948-6953G>C
NM_002474.2:c.5406C>G

Protein change:

H1802Q

Links:

dbSNP: rs746211825

NCBI 1000 Genomes Browser:

rs746211825

Molecular consequence:

NM_001143979.2:c.948-6953G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_017668.3:c.948-6953G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001040113.2:c.5427C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001040114.2:c.5427C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002474.3:c.5406C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_022844.3:c.5406C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Aortic aneurysm, familial thoracic 4 (AAT4)
Synonyms:: AORTIC ANEURYSM/AORTIC DISSECTION AND PATENT DUCTUS ARTERIOSUS
Identifiers:: MONDO: MONDO:0007568; MedGen: C1851504; OMIM: 132900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000763218	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001275739	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000763218

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 7, 2024)

germline

clinical testing

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

SCV001275739

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000763218.5

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

Description

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1809 of the MYH11 protein (p.His1809Gln). This variant is present in population databases (rs746211825, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 318095). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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 Illumina Laboratory Services, Illumina, SCV001275739.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 3, 2025

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