This variant is interpreted as a Likely Benign, for Aortic aneurysm, familial thoracic 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:27146836). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS2-Supporting => BS2 downgraded in strength to supporting.
ClinVar Genomic variation as it relates to human health
NM_053025.4(MYLK):c.1133G>A (p.Arg378His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(3)
Uncertain significance(4); Likely benign(3)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_053025.4(MYLK):c.1133G>A (p.Arg378His)
Variation ID: 264282 Accession: VCV000264282.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q21.1 3: 123733863 (GRCh38) [ NCBI UCSC ] 3: 123452710 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Oct 20, 2024 Jan 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_053025.4:c.1133G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_444253.3:p.Arg378His missense NM_001321309.2:c.605G>A NP_001308238.1:p.Arg202His missense NM_053026.4:c.1133G>A NP_444254.3:p.Arg378His missense NM_053027.4:c.1133G>A NP_444255.3:p.Arg378His missense NM_053028.4:c.1133G>A NP_444256.3:p.Arg378His missense NC_000003.12:g.123733863C>T NC_000003.11:g.123452710C>T NG_029111.1:g.155440G>A Q15746:p.Arg378His - Protein change
- R378H, R202H
- Other names
-
NM_053025.3(MYLK):c.1133G>A(p.Arg378His)
NM_053026.3(MYLK):c.1133G>A(p.Arg378His)
NM_053027.3(MYLK):c.1133G>A(p.Arg378His)
NM_053028.3(MYLK):c.1133G>A(p.Arg378His)
- Canonical SPDI
- NC_000003.12:123733862:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00014
Trans-Omics for Precision Medicine (TOPMed) 0.00014
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MYLK | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1817 | 2159 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 4, 2022 | RCV000477018.21 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 11, 2023 | RCV000999540.29 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jun 24, 2022 | RCV002311120.12 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely benign
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Aortic aneurysm, familial thoracic 7
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803574.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
Comment:
This variant is interpreted as a Likely Benign, for Aortic aneurysm, familial thoracic 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 … (more)
This variant is interpreted as a Likely Benign, for Aortic aneurysm, familial thoracic 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:27146836). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS2-Supporting => BS2 downgraded in strength to supporting. (less)
|
|
|
Uncertain significance
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 7
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001311716.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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 … (more)
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. (less)
|
|
|
Uncertain significance
(Oct 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Aortic aneurysm, familial thoracic 7
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000550031.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the MYLK protein (p.Arg378His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the MYLK protein (p.Arg378His). This variant is present in population databases (rs56378658, gnomAD 0.02%). This missense change has been observed in individual(s) with thoracic aortic aneurysms and dissections (PMID: 27146836). ClinVar contains an entry for this variant (Variation ID: 264282). 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. (less)
|
|
|
Likely benign
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000320102.7
First in ClinVar: Oct 03, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Likely benign
(Mar 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001156212.27
First in ClinVar: Feb 06, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002540520.2
First in ClinVar: Jul 09, 2022 Last updated: Jan 21, 2023 |
Comment:
Reported as a likely benign variant in one individual diagnosed with TAAD and did not segregate with disease in this individual's family (Poninska et al., … (more)
Reported as a likely benign variant in one individual diagnosed with TAAD and did not segregate with disease in this individual's family (Poninska et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146836) (less)
|
|
|
Uncertain significance
(Apr 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003837878.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927670.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973687.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
Comment:
Comment:
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.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the MYLK protein (p.Arg378His). This variant is present in population databases (rs56378658, gnomAD 0.02%). This missense change has been observed in individual(s) with thoracic aortic aneurysms and dissections (PMID: 27146836). ClinVar contains an entry for this variant (Variation ID: 264282). 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.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Reported as a likely benign variant in one individual diagnosed with TAAD and did not segregate with disease in this individual's family (Poninska et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146836)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant is interpreted as a Likely Benign, for Aortic aneurysm, familial thoracic 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:27146836). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS2-Supporting => BS2 downgraded in strength to supporting.
Comment:
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.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the MYLK protein (p.Arg378His). This variant is present in population databases (rs56378658, gnomAD 0.02%). This missense change has been observed in individual(s) with thoracic aortic aneurysms and dissections (PMID: 27146836). ClinVar contains an entry for this variant (Variation ID: 264282). 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.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Reported as a likely benign variant in one individual diagnosed with TAAD and did not segregate with disease in this individual's family (Poninska et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146836)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. | Poninska JK | Journal of translational medicine | 2016 | PMID: 27146836 |
| 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 | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Text-mined citations for rs56378658 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.