NM_053025.4(MYLK):c.2149G>A (p.Asp717Asn) AND Aortic aneurysm, familial thoracic 7

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 25, 2022
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:: RCV000648721.17

Allele description [Variation Report for NM_053025.4(MYLK):c.2149G>A (p.Asp717Asn)]

NM_053025.4(MYLK):c.2149G>A (p.Asp717Asn)

Gene:

MYLK:myosin light chain kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q21.1

Genomic location:

Preferred name:

NM_053025.4(MYLK):c.2149G>A (p.Asp717Asn)

HGVS:

NC_000003.12:g.123707995C>T
NG_029111.1:g.181308G>A
NM_001321309.2:c.1621G>A
NM_053025.4:c.2149G>AMANE SELECT
NM_053026.4:c.1942G>A
NM_053027.4:c.2149G>A
NM_053028.4:c.1942G>A
NP_001308238.1:p.Asp541Asn
NP_444253.3:p.Asp717Asn
NP_444254.3:p.Asp648Asn
NP_444255.3:p.Asp717Asn
NP_444256.3:p.Asp648Asn
NC_000003.11:g.123426842C>T
NM_053025.3:c.2149G>A

Protein change:

D541N

Links:

dbSNP: rs150936840

NCBI 1000 Genomes Browser:

rs150936840

Molecular consequence:

NM_001321309.2:c.1621G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_053025.4:c.2149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_053026.4:c.1942G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_053027.4:c.2149G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_053028.4:c.1942G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Aortic aneurysm, familial thoracic 7 (AAT7)
Synonyms:: AORTIC DISSECTION, FAMILIAL, WITH OR WITHOUT AORTIC ANEURYSM
Identifiers:: MONDO: MONDO:0013418; MedGen: C3151077; OMIM: 613780

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000770542	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30755392, 28492532
SCV000898844	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 8, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000770542

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 25, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000898844

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 8, 2018)

germline

clinical testing

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

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

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants.

Ji J, Shen L, Bootwalla M, Quindipan C, Tatarinova T, Maglinte DT, Buckley J, Raca G, Saitta SC, Biegel JA, Gai X.

Cold Spring Harb Mol Case Stud. 2019 Apr 1;5(2). doi:pii: a003756. 10.1101/mcs.a003756. Print 2019 Apr.

PubMed [citation]

PMID:: 30755392
PMCID:: PMC6549575

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000770542.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 717 of the MYLK protein (p.Asp717Asn). This variant is present in population databases (rs150936840, gnomAD 0.04%). This missense change has been observed in individual(s) with aortic dissection (PMID: 30755392). ClinVar contains an entry for this variant (Variation ID: 519975). 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 MYLK protein function. 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 Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000898844.1

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

Description

MYLK NM_053025.3 exon 16 p.Asp717Asn (c.2149G>A): This variant has not been reported in the literature but is present in 13/34408 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs150936840). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

#	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 20, 2024

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