Submissions for variant NM_002474.3(MYH11):c.3757AAG[3] (p.Lys1256del)

dbSNP: rs730880147

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254668	SCV000234904	uncertain significance	not provided	2024-10-08	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid with an unclear effect on protein function; In silico analysis supports a deleterious effect on protein structure/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, 37894894, 37042257)
Ambry Genetics	RCV000157334	SCV000319471	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-02-12	criteria provided, single submitter	clinical testing	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). Mouse models for this alteration demonstrate an impact (Negishi K et al. Sci Rep, 2022 May;12:8844; Tomida S et al. Int J Mol Sci, 2023 Oct;24:). 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). Based on the supporting evidence, this variant is expected to be causative of MYH11-related thoracic aortic aneurysm and dissection (TAAD), though it may represent a lower penetrance allele; however, its clinical significance for MYH11-related megacystis-microcolon-intestinal hypoperistalsis syndrome is unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466385	SCV000543703	pathogenic	Aortic aneurysm, familial thoracic 4	2025-01-20	criteria provided, single submitter	clinical testing	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; internal data). 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 gene product 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.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000157334	SCV000897677	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-11-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254668	SCV001150826	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000157334	SCV001333993	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000157334	SCV001340636	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-28	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157334	SCV002570673	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-16	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000254668	SCV003817170	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000466385	SCV004242389	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-01-09	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM4,PS3_SUP
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157334	SCV004847641	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-04-19	criteria provided, single submitter	clinical testing	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.
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV000466385	SCV005050140	likely pathogenic	Aortic aneurysm, familial thoracic 4	2024-05-08	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000254668	SCV005199272	likely pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000466385	SCV005399374	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (MMIHS; MIM#619351). The disease mechanism for chronic intestinal pseudo-obstruction (CIPO), also known as visceral myopathy 2 (MIM#619350), and aortic aneurysm, familial thoracic 4 (AAFT; MIM#132900) is unclear, however loss of function and dominant negative have been suggested, respectively (PMID: 31944481). (I) 0108 - This gene is associated with both recessive and dominant disease. MMIHS is an autosomal recessive form of disease caused by both missense variants and those resulting in a premature termination codon. AAFT is autosomal dominant and has been reported in patients with splice, missense and inframe deletion variants. CIPO is autosomal dominant and has only been reported in patients with protein elongation variants exclusive to isoform SM2 (PMIDs: 31389005, 31944481). (I) 0112 - The aortic aneurysm associated with this gene has incomplete penetrance (PMIDs: 17666408, 22968129). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 15 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated myosin tail 1 domain (DECIPHER). (I) 0705 - No comparable deletion have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as a VUS or likely pathogenic/pathogenic, and in at least 17 unrelated individuals with MYH11-related conditions including patent ductus arteriosus (PDA), thoracic aortic aneurysms and dissections (TAAD), and sudden death. One patient with aortic dissection has a diagnosis of Marfan syndrome associated with a pathogenic variant in FBN1, in addition to harbouring the MYH11 variant (VCGS, ClinVar, PMIDs: 26056961, 22968129, 28391405, 25944730, 34422331, 29510914, 30675029, 29907982, 28074631, 19875725, 25907466). (SP) 0906 - Segregation evidence for this variant is inconclusive. It fully segregated with PDA/TAAD in one of the families reported (PMID: 26056961), however another family demonstrated incomplete penetrance (PMID: 22968129). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mouse model with heterozygous p.(Lys1256del) developed aortic dissections and intramural haematomas when stimulated with angiotensin II (PMID: 35614093). The authors concluded that the variant leads to structural fragility and maladaptation against mechanical stress in aortas by decreasing the composition of elastin lamellae and smooth muscle cell contractility. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Blueprint Genetics	RCV000157334	SCV000207071	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2014-09-18	no assertion criteria provided	clinical testing
Heart Medical Centre, First Affiliated Hospital of Gannan Medical University	RCV003228908	SCV003926547	pathogenic	Congenital aneurysm of ascending aorta	2021-12-28	no assertion criteria provided	clinical testing