ClinVar Genomic variation as it relates to human health
NM_002474.3(MYH11):c.3757AAG[3] (p.Lys1256del)
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.
Pathogenic(2); Likely pathogenic(2); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002474.3(MYH11):c.3757AAG[3] (p.Lys1256del)
Variation ID: 180420 Accession: VCV000180420.51
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 16p13.11 16: 15726938-15726940 (GRCh38) [ NCBI UCSC ] 16: 15820795-15820797 (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 Feb 7, 2015 Apr 20, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002474.3:c.3757AAG[3] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002465.1:p.Lys1256del inframe deletion NM_002474.3:c.3766_3768del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001040113.2:c.3778AAG[3] MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035202.1:p.Lys1263del inframe deletion NM_001040113.2:c.3787_3789del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001040113.2:c.3787_3789delAAG MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001040113.1:c.3787_3789del NM_001040114.1:c.3787_3789delAAG NM_001040114.2:c.3778AAG[3] NP_001035203.1:p.Lys1263del inframe deletion NM_001040114.2:c.3787_3789delAAG NM_002474.2:c.3766_3768delAAG NM_022844.3:c.3757AAG[3] NP_074035.1:p.Lys1256del inframe deletion NC_000016.10:g.15726938CTT[3] NC_000016.9:g.15820795CTT[3] NG_009299.1:g.135082AAG[3] NG_021210.1:g.88672CTT[3] LRG_1401:g.135082AAG[3] LRG_1401t1:c.3757AAG[3] LRG_1401p1:p.Lys1256del LRG_1401t2:c.3778AAG[3] LRG_1401p2:p.Lys1263del - Protein change
- K1263del, K1256del
- Other names
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- Canonical SPDI
- NC_000016.10:15726937:CTTCTTCTTCTT:CTTCTTCTT
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
1988 | 3711 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Jan 16, 2024 | RCV000157334.27 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 27, 2023 | RCV000254668.30 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000466385.17 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 28, 2021 | RCV003228908.8 |
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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Likely pathogenic
(Nov 20, 2018)
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criteria provided, single submitter
(ACMG Guidelines, 2015)
Method: clinical testing
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Thoracic aortic aneurysm and aortic dissection
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Medical Center Hamburg-Eppendorf
Accession: SCV000897677.1
First in ClinVar: Apr 17, 2019 Last updated: Apr 17, 2019 |
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Uncertain significance
(Jan 20, 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: SCV000319471.7
First in ClinVar: Oct 02, 2016 Last updated: Apr 15, 2023 |
Comment:
The c.3766_3768delAAG variant (also known as p.K1256del) is located in coding exon 27 of the MYH11 gene. This variant results from an in-frame AAG deletion … (more)
The c.3766_3768delAAG variant (also known as p.K1256del) is located in coding exon 27 of the MYH11 gene. This variant results from an in-frame AAG deletion at nucleotide positions 3766 to 3768. This results in the in-frame deletion of a lysine at codon 1256. This variant, sometimes described as c.3787_3789delAAG (p.K1236del), has been reported in individuals with thoracic aortic aneurysms and dissections (TAAD) and patent ductus arteriosus (PDA), including segregation with disease in at least one family (Proost D et al. Hum. Mutat., 2015 Aug;36:808-14; Imai Y et al. Int. J. Cardiol., 2015 Sep;195:290-2; Yeung KK et al. Hum. Mutat., 2017 Apr;38:439-450; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; Ambry internal data). In another large family affected with TAAD and PDA, eight affected family members were found to carry this variant, while three affected family members tested negative for the variant (Harakalova M, Eur. J. Hum. Genet. 2013 May; 21(5):487-93). In addition, this alteration was identified twice in a cohort of individuals referred for aortopathy panel testing, one of whom had aortic dilation and dissection and also carried the FBN1 p.T2149Ifs*11 mutation (Wooderchak-Donahue W et al. Am. J. Med. Genet. A, 2015 Aug;167A:1747-57). A mouse model for this alteration demonstrated a conflicting impact (Negishi K et al. Sci Rep, 2022 May;12:8844). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Oct 27, 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: SCV000234904.13
First in ClinVar: Jul 05, 2015 Last updated: Nov 25, 2023 |
Comment:
In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of one amino acid with an unclear effect on protein function; This variant … (more)
In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of one amino acid with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 18391202, 29907982, 28391405, 30675029, 34426522, 25907466, 22968129, 34422331, 28074631, TomidaS2023[Article], PortelliS2023[Preprint], 29510914, 37644562, 35614093, 36307044, 37426142, 26056961, 25944730) (less)
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Uncertain significance
(Mar 04, 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: SCV003817170.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(May 23, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333993.4
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Aortic aneurysm, familial thoracic 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004242389.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PS4_MOD,PM4,PS3_SUP
Clinical Features:
Aortic dissection (present)
Sex: female
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Uncertain significance
(Feb 28, 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: SCV001340636.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes a deletion of lysine at codon 1263 of the MYH11 protein. This variant is also known as c.3766_3768delAAG, p.Lys1256del based on a … (more)
This variant causes a deletion of lysine at codon 1263 of the MYH11 protein. This variant is also known as c.3766_3768delAAG, p.Lys1256del based on a different transcript NM_002474.2. A functional study has shown that this variant has subtle impact on the subcellular localization of MYH11 protein (PMID: 28074631), however, clinical relevance of this observation is not clear. This variant has been reported in four individuals from three families, who were affected with thoracic aortic aneurysms (PMID: 22968129, 26056961). However, in one of these families, this variant was not detected in an affected family member (PMID: 22968129). This variant has been reported in several unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 25907466, 28074631, 28391405, 29510914, 29907982, 30675029, doi.org/10.21203/rs.3.rs-1548216/v1), as well as in two individuals referred for aortopathy genetic testing (PMID: 25944730). This variant has also been identified in 13/282182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been observed in multiple affected individuals, it has also been observed in the general population, and family studies are inconclusive as to whether this variant segregates with the observed phenotype. 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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Pathogenic
(Jan 29, 2024)
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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: SCV000543703.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant, c.3787_3789del, results in the deletion of 1 amino acid(s) of the MYH11 protein (p.Lys1263del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.3787_3789del, results in the deletion of 1 amino acid(s) of the MYH11 protein (p.Lys1263del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with clinical features of autosomal dominant MYH11-related conditions (PMID: 22968129, 25944730, 26056961, 29907982, 30675029; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3766_3768delAAG (p.Lys1256del). ClinVar contains an entry for this variant (Variation ID: 180420). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MYH11 function (PMID: 28074631). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 16, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570673.2
First in ClinVar: Sep 17, 2022 Last updated: Mar 30, 2024 |
Comment:
Variant summary: MYH11 c.3787_3789delAAG (p.Lys1263del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more)
Variant summary: MYH11 c.3787_3789delAAG (p.Lys1263del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 3.5e-05 in 1613080 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05). While this typically suggests that the variant is a benign polymorphism, due to variable age of onset, no conclusions can be made regarding variant significance. c.3787_3789delAAG has been reported in the literature in multiple individuals affected with Thoracic Aortic Aneurysms And Dissections, and Patent Ductus Arteriosus (e.g. Harakalova_2013, Imai_2015, Wooderchack-Donahue_2015, Yeung_2017, Overwater_2018, Hicks_2018, Renner_2019, Duan_2023). Segregation data is present for several families. In one family with four individuals affected with PDA and two affected with TAAD, there was one individual with PDA and one individual with TAAD who did not have this variant, suggesting lack of segregation (Harakalova_2013). However in a second family, all affected members carried the variant (n=3) while unaffected members (n=4) did not (Imai_2015). A co-occurrence with at least one other pathogenic variant has been reported (FBN1 c.6664delC, p.Tyr2149fs; Wooderchack-Donahue_2015). A publication reports experimental evidence evaluating an impact on protein function in a mouse model and found that heterozygous mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II, although without stimulation neither heterozygous nor homozygous mice experienced aortic dissection when observed for a period of over 18 months (Negishi_2022). Additionally, transdifferentiated smooth muscle cells derived from an aortic aneurysm patient with the variant were found to have abnormal contractile cytoskeleton formation compared to cells from patients without a proven pathogenic variant and healthy controls (Yeung_2017). The following publications have been ascertained in the context of this evaluation (PMID: 37644562, 22968129, 29510914, 26056961, 35614093, 29907982, 30675029, 25944730, 28074631). ClinVar contains an entry for this variant (Variation ID: 180420). Based on the conflicting nature of the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jun 01, 2017)
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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: SCV001150826.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Uncertain Significance
(Apr 19, 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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847641.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Lys1263del variant in MYH11 (also reported as p.Lys1256del) has been reported in 8 individuals with thoracic aortic dissection (including aneurysm) (Harakalova 2013, Imai 2015, … (more)
The p.Lys1263del variant in MYH11 (also reported as p.Lys1256del) has been reported in 8 individuals with thoracic aortic dissection (including aneurysm) (Harakalova 2013, Imai 2015, Yeung 2017, Overwater 2018, Wooderchack-Donahue 2015) and segregated with disease in 1 individual affected with thoracic aortic dissection from 1 family and 4 individuals affected with PDA from 2 families (Harakalova 2013, Imai 2015). However, this variant was shown not to segregate with disease in 1 individual affected with PDA and in 1 individual affected with thoracic aortic dissection from 1 family, though the individual with aortic dissection was more distantly related (Harlakova 2013). This variant has also been reported in ClinVar (Variation ID 180420). It has been identified in 11 individuals referred for Marfan/TAAD testing at GeneDx, but in 3 of these cases other variants in additional genes were reported (GeneDx personal communication). It has also been identified in 0.007% (9/129114) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 1263 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. Computational prediction tools and conservation analysis suggest that this variant may impact the protein and in vitro functional studies provide some evidence that this variant impacts protein function (Yeung 2017); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PS4_Moderate, PM4_Supporting, BP5. (less)
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Uncertain significance
(Sep 18, 2014)
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no assertion criteria provided
Method: clinical testing
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Thoracic aortic aneurysms and aortic dissections
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000207071.2
First in ClinVar: Feb 07, 2015 Last updated: Apr 15, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 28, 2021)
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no assertion criteria provided
Method: clinical testing
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Congenital aneurysm of ascending aorta
Affected status: yes
Allele origin:
unknown
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Heart Medical Centre, First Affiliated Hospital of Gannan Medical University
Accession: SCV003926547.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
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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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Analysis of the genetic contribution to thoracic aortic aneurysm or dissection in a prospective cohort of patients with familial and sporadic cases in East China. | Duan Y | Orphanet journal of rare diseases | 2023 | PMID: 37644562 |
An Myh11 single lysine deletion causes aortic dissection by reducing aortic structural integrity and contractility. | Negishi K | Scientific reports | 2022 | PMID: 35614093 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Genetic variants in Chinese patients with sporadic Stanford type A aortic dissection. | Chen ZR | Journal of thoracic disease | 2021 | PMID: 34422331 |
Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. | Renner S | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30675029 |
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 |
Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center. | Hicks KL | Journal of vascular surgery | 2018 | PMID: 29510914 |
Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection. | Gago-Díaz M | International journal of legal medicine | 2017 | PMID: 28391405 |
Transdifferentiation of Human Dermal Fibroblasts to Smooth Muscle-Like Cells to Study the Effect of MYH11 and ACTA2 Mutations in Aortic Aneurysms. | Yeung KK | Human mutation | 2017 | PMID: 28074631 |
A deletion mutation in myosin heavy chain 11 causing familial thoracic aortic dissection in two Japanese pedigrees. | Imai Y | International journal of cardiology | 2015 | PMID: 26056961 |
Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. | Wooderchak-Donahue W | American journal of medical genetics. Part A | 2015 | PMID: 25944730 |
Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. | Proost D | Human mutation | 2015 | PMID: 25907466 |
Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus. | Harakalova M | European journal of human genetics : EJHG | 2013 | PMID: 22968129 |
Unregulated smooth-muscle myosin in human intestinal neoplasia. | Alhopuro P | Proceedings of the National Academy of Sciences of the United States of America | 2008 | PMID: 18391202 |
Specific effects of blood plasma from beef cows fed pine needles during late pregnancy on increasing tone of caruncular arteries in vitro. | Christenson LK | Journal of animal science | 1992 | PMID: 1548216 |
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Text-mined citations for rs730880147 ...
HelpRecord last updated Apr 20, 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.