NM_053025.4(MYLK):c.3610C>T (p.Arg1204Trp) AND Aortic aneurysm, familial thoracic 7

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 26, 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:: RCV000460022.13

Allele description [Variation Report for NM_053025.4(MYLK):c.3610C>T (p.Arg1204Trp)]

NM_053025.4(MYLK):c.3610C>T (p.Arg1204Trp)

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.3610C>T (p.Arg1204Trp)

HGVS:

NC_000003.12:g.123682266G>A
NG_029111.1:g.207037C>T
NM_001321309.2:c.3082C>T
NM_053025.4:c.3610C>TMANE SELECT
NM_053026.4:c.3403C>T
NM_053027.4:c.3610C>T
NM_053028.4:c.3403C>T
NP_001308238.1:p.Arg1028Trp
NP_444253.3:p.Arg1204Trp
NP_444254.3:p.Arg1135Trp
NP_444255.3:p.Arg1204Trp
NP_444256.3:p.Arg1135Trp
NC_000003.11:g.123401113G>A
NM_053025.3:c.3610C>T

Protein change:

R1028W

Links:

dbSNP: rs151294221

NCBI 1000 Genomes Browser:

rs151294221

Molecular consequence:

NM_001321309.2:c.3082C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_053025.4:c.3610C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_053026.4:c.3403C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_053027.4:c.3610C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_053028.4:c.3403C>T - 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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Escherichia coli strain:2461 | isolate:2461
Escherichia coli strain:2461 | isolate:2461
Escherichia coli strain:2461 | isolate:2461 Genome sequencing

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000440294	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000550029	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28139901, 29907982, 28492532
SCV004704535	Human Genetics Bochum, Ruhr University Bochum	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28139901, 29907982, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000440294

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV000550029

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004704535

Human Genetics Bochum, Ruhr University Bochum

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Clinical and genetic characterization of adult patients presenting with non-syndromic vascular aneurysms and dissections.

D'Souza RS, Slavov D, Graw S, Jirikowic J, Todd E, Rogers RK, Taylor MR.

Int Angiol. 2017 Oct;36(5):417-427. doi: 10.23736/S0392-9590.17.03757-9. Epub 2017 Jan 31.

PubMed [citation]

PMID:: 28139901

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000440294.3

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000550029.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1204 of the MYLK protein (p.Arg1204Trp). This variant is present in population databases (rs151294221, gnomAD 0.02%). This missense change has been observed in individual(s) with MYLK-related conditions (PMID: 28139901, 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 342881). 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 with a negative predictive value of 80%. 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 Human Genetics Bochum, Ruhr University Bochum, SCV004704535.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ACMG criteria used to clasify this variant: PP3SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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