ClinVar Genomic variation as it relates to human health
NM_002474.3(MYH11):c.4861A>C (p.Lys1621Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002474.3(MYH11):c.4861A>C (p.Lys1621Gln)
Variation ID: 36622 Accession: VCV000036622.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.11 16: 15720243 (GRCh38) [ NCBI UCSC ] 16: 15814100 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 May 12, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002474.3:c.4861A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002465.1:p.Lys1621Gln missense NM_017668.3:c.948-3948T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001040113.2:c.4882A>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035202.1:p.Lys1628Gln missense NM_001040114.2:c.4882A>C NP_001035203.1:p.Lys1628Gln missense NM_001143979.2:c.948-3948T>G intron variant NM_022844.3:c.4861A>C NP_074035.1:p.Lys1621Gln missense NC_000016.10:g.15720243T>G NC_000016.9:g.15814100T>G NG_009299.1:g.141788A>C NG_021210.1:g.81977T>G LRG_1401:g.141788A>C LRG_1401t1:c.4861A>C LRG_1401p1:p.Lys1621Gln LRG_1401t2:c.4882A>C LRG_1401p2:p.Lys1628Gln - Protein change
- K1628Q, K1621Q
- Other names
- p.K1621Q:AAG>CAG
- Canonical SPDI
- NC_000016.10:15720242:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
The Genome Aggregation Database (gnomAD) 0.00011
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 | ||
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HI score
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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. |
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MYH11 | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh37 |
2008 | 3752 | |
NDE1 | - | - |
GRCh38 GRCh38 GRCh37 |
178 | 1922 |
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Oct 19, 2020 | RCV000182562.12 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2022 | RCV000554857.15 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV000611869.20 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 1, 2016 | RCV000659924.8 | |
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV000762209.33 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 27, 2021 | RCV002482921.8 |
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. |
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Uncertain significance
(Feb 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 4
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000744016.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Uncertain significance
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Connective tissue disorder
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781828.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 4
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139961.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Dec 11, 2019)
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criteria provided, single submitter
Method: research
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Aortic aneurysm, familial thoracic 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Cavalleri Lab, Royal College of Surgeons in Ireland
Accession: SCV001160810.1
First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020 |
Comment:
ACMG evidence PP2, PP3, PP5
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Uncertain significance
(Feb 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333418.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Uncertain significance
(Oct 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 4
Visceral myopathy 2 Megacystis-microcolon-intestinal hypoperistalsis syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002780792.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Sep 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 4
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000641058.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1628 of the MYH11 protein (p.Lys1628Gln). … (more)
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1628 of the MYH11 protein (p.Lys1628Gln). This variant is present in population databases (rs34321232, gnomAD 0.02%). This missense change has been observed in individual(s) with aortic aneurysm (PMID: 29543232, 29907982). ClinVar contains an entry for this variant (Variation ID: 36622). 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. 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)
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Uncertain significance
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234912.15
First in ClinVar: Jul 05, 2015 Last updated: Jun 10, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(K1628Q); This variant is associated with the … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(K1628Q); This variant is associated with the following publications: (PMID: 29907982, 32238909, 20226094, 29543232) (less)
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Uncertain significance
(Apr 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892483.23
First in ClinVar: Mar 31, 2019 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Feb 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 4
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745958.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987635.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
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Uncertain significance
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052967.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2020 |
Comment:
Variant summary: MYH11 c.4882A>C (p.Lys1628Gln) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of … (more)
Variant summary: MYH11 c.4882A>C (p.Lys1628Gln) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251470 control chromosomes. The observed variant frequency is approximately 79.5- fold the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. c.4882A>C has been reported in the literature in individuals affected with aneurysm and thoracic aortic disease (examples- Weerakkody_2018, Overwater_2018). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Jan 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003817183.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Apr 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001354763.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with thoracic aortic aneurysm (PMID: 29907982, 29543232), in an individual affected with sudden unexplained death (PMID: 35276540), and in another individual affected with atrioventricular septal defect (PMID: 35393538). This variant has been identified in 29/282846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004821166.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with thoracic aortic aneurysm (PMID: 29907982, 29543232), in an individual affected with sudden unexplained death (PMID: 35276540), and in another individual affected with atrioventricular septal defect (PMID: 35393538). This variant has also been identified in 29/282846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 39
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Uncertain significance
(Jul 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000739203.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.K1621Q variant (also known as c.4861A>C), located in coding exon 33 of the MYH11 gene, results from an A to C substitution at nucleotide … (more)
The p.K1621Q variant (also known as c.4861A>C), located in coding exon 33 of the MYH11 gene, results from an A to C substitution at nucleotide position 4861. The lysine at codon 1621 is replaced by glutamine, an amino acid with similar properties, and is located in the coiled coil domain. This variant was detected in an individual with a thoracic aortic aneurysm (TAAD) and no known family history of the condition; however, clinical details were limited (Weerakkody R et al. Genet. Med., 2018 Nov;20:1414-1422). This alteration was also reported in a sudden unexplained death cohort (Neubauer J et al. Forensic Sci Int, 2022 May;334:111240). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: yes
Allele origin:
unknown
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Centre for Genomic and Experimental Medicine, University of Edinburgh
Accession: SCV000731234.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Clinical Features:
Aneurysm (present)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001973996.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550154.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MYH11 p.K1621Q variant was identified in an individual with thoracic aortic aneurysm/aortic dissection and an individual with suspected hereditary thoracic aortic disease (Weerakkody_2018_ PMID: … (more)
The MYH11 p.K1621Q variant was identified in an individual with thoracic aortic aneurysm/aortic dissection and an individual with suspected hereditary thoracic aortic disease (Weerakkody_2018_ PMID: 29543232; Overwater_2018_ PMID: 29907982). This variant was also identified in an individual with generalized epilepsy inherited from a presumably unaffected father without a family history of epilepsy (Benson_2020_PMID: 32238909). The variant was identified in dbSNP (ID: rs34321232) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and ten other submitters; and as likely pathogenic by Centre for Genomic and Experimental Medicine, University of Edinburgh). The variant was identified in control databases in 29 of 282846 chromosomes at a frequency of 0.0001025, and was observed at the highest frequency in the European (non-Finnish) population in 27 of 129166 chromosomes (freq: 0.0002090) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.K1621 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Abstracts from the 54(th) European Society of Human Genetics (ESHG) Conference: e-Posters. | - | European journal of human genetics : EJHG | 2022 | PMID: 35393538 |
Benefits and outcomes of a new multidisciplinary approach for the management and financing of sudden unexplained death cases in a forensic setting in Switzerland. | Neubauer J | Forensic science international | 2022 | PMID: 35276540 |
A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability. | Benson KA | European journal of human genetics : EJHG | 2020 | PMID: 32238909 |
Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. | Overwater E | Human mutation | 2018 | PMID: 29907982 |
Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. | Weerakkody R | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29543232 |
Text-mined citations for rs34321232 ...
HelpRecord last updated May 27, 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.