16-15726937-GCTT-G

Position:

• chr16-15726937-GCTT-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4_Supporting PP5

The NM_002474.3(MYH11):​c.3766_3768del​(p.Lys1256del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000347 in 1,613,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MYH11 NM_002474.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:7
• Conservation: PhyloP100: 6.26

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

(HGNC:):

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002474.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-15726937-GCTT-G is Pathogenic according to our data. Variant chr16-15726937-GCTT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180420.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=7, Pathogenic=2}. Variant chr16-15726937-GCTT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_001040113.2	c.3787_3789del	p.Lys1263del	inframe_deletion	29/43	ENST00000452625.7	NP_001035202.1
MYH11	NM_002474.3	c.3766_3768del	p.Lys1256del	inframe_deletion	28/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040114.2	c.3787_3789del	p.Lys1263del	inframe_deletion	29/42		NP_001035203.1
MYH11	NM_022844.3	c.3766_3768del	p.Lys1256del	inframe_deletion	28/42		NP_074035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3766_3768del	p.Lys1256del	inframe_deletion	28/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.3787_3789del	p.Lys1263del	inframe_deletion	29/43	1	NM_001040113.2	ENSP00000407821
	ENST00000574212.1	n.274_276del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151834 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 250872 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135660

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461128 Hom.: 0 AF XY: 0.0000371 AC XY: 27 AN XY: 726876

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151952 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74256

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	Nov 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 23, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 18, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2024	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. -

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -

Aortic aneurysm, familial thoracic 4 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 09, 2024	Criteria applied: PS4_MOD,PM4,PS3_SUP -
Likely pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	May 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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. -

Congenital aneurysm of ascending aorta Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Heart Medical Centre, First Affiliated Hospital of Gannan Medical University

Dec 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880147; hg19: chr16-15820794;