NM_002474.3(MYH11):c.5275G>A (p.Val1759Ile) AND Aortic aneurysm, familial thoracic 4

Germline classification:
Uncertain significance (3 submissions)
Last evaluated:
Jan 29, 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:
RCV000239107.22

Allele description [Variation Report for NM_002474.3(MYH11):c.5275G>A (p.Val1759Ile)]

NM_002474.3(MYH11):c.5275G>A (p.Val1759Ile)

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.5275G>A (p.Val1759Ile)
Other names:
p.V1759I:GTC>ATC
HGVS:
  • NC_000016.10:g.15718335C>T
  • NG_009299.1:g.143696G>A
  • NG_021210.1:g.80069C>T
  • NM_001040113.2:c.5296G>A
  • NM_001040114.2:c.5296G>A
  • NM_001143979.2:c.948-5856C>T
  • NM_002474.3:c.5275G>AMANE SELECT
  • NM_017668.3:c.948-5856C>TMANE SELECT
  • NM_022844.3:c.5275G>A
  • NP_001035202.1:p.Val1766Ile
  • NP_001035203.1:p.Val1766Ile
  • NP_002465.1:p.Val1759Ile
  • NP_074035.1:p.Val1759Ile
  • LRG_1401t1:c.5275G>A
  • LRG_1401t2:c.5296G>A
  • LRG_1401:g.143696G>A
  • LRG_1401p1:p.Val1759Ile
  • LRG_1401p2:p.Val1766Ile
  • NC_000016.9:g.15812192C>T
  • NM_001040113.1:c.5296G>A
  • NM_001143979.1:c.948-5856C>T
  • NM_002474.2:c.5275G>A
Protein change:
V1759I
Links:
dbSNP: rs138059405
NCBI 1000 Genomes Browser:
rs138059405
Molecular consequence:
  • NM_001143979.2:c.948-5856C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_017668.3:c.948-5856C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001040113.2:c.5296G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001040114.2:c.5296G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002474.3:c.5275G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_022844.3:c.5275G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000296988Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
criteria provided, single submitter

(DGD Variant Analysis Guidelines)
Uncertain significance
(Oct 30, 2015)
unknownclinical testing

DGD_Variant_Analysis_Guidelines.docx,

Citation Link,

SCV000641068Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 29, 2024)
germlineclinical testing

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

SCV001277493Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000296988.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000641068.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1766 of the MYH11 protein (p.Val1766Ile). This variant is present in population databases (rs138059405, gnomAD 0.05%). 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: 201037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV001277493.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024