rs201831933

Positions:

• chr16-15726915-A-G
• chr16-15726915-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_002474.3(MYH11):​c.3791T>C​(p.Leu1264Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1264V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 16-15726915-A-G is Pathogenic according to our data. Variant chr16-15726915-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 88953.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.3791T>C	p.Leu1264Pro	missense_variant	28/41	ENST00000300036.6
MYH11	NM_001040113.2	c.3812T>C	p.Leu1271Pro	missense_variant	29/43	ENST00000452625.7
MYH11	NM_001040114.2	c.3812T>C	p.Leu1271Pro	missense_variant	29/42
MYH11	NM_022844.3	c.3791T>C	p.Leu1264Pro	missense_variant	28/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3791T>C	p.Leu1264Pro	missense_variant	28/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3812T>C	p.Leu1271Pro	missense_variant	29/43	1	NM_001040113.2
	ENST00000574212.1	n.242A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 22, 2021	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to segregate with thoracic aortic aneurysm and dissection in families (PMID: 17666408, 27081537) and has been observed in an individual affected with this disease (Invitae). This variant is also known as L1264P in the literature. ClinVar contains an entry for this variant (Variation ID: 88953, 440783). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1271 of the MYH11 protein (p.Leu1271Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2024

The p.L1264P pathogenic mutation (also known as c.3791T>C), located in coding exon 27 of the MYH11 gene, results from a T to C substitution at nucleotide position 3791. The leucine at codon 1264 is replaced by proline, an amino acid with similar properties. This variant has segregated with disease in a family with thoracic aortic aneurysm and dissection (TAAD) and patent ductus arteriosus (PDA) and was suggested to be in linkage disequilibrium with a second MYH11 missense variant, both located in the coiled-coil domain. The p.L1264P alteration was predicted to introduce a helix breaking residue (proline), disrupting the coiled-coil formation (Pannu H et al. Hum Mol Genet. 2007;16(20):2453-2462). This variant has also segregated with disease in a second family with TAAD (Takeda N et al. Hum Genome Var. 2015 Aug;2:15028). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of MYH11-related thoracic aortic aneurysm and dissection; however, its clinical significance for MYH11-related megacystis-microcolon-intestinal hypoperistalsis syndrome is unclear. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2015

p.Leu1264Pro (CTG>CCG): c.3791 T>C in exon 28 of the MYH11 gene (NM_002474.2)The L1264P mutation in the MYH11 gene has been reported in one family in association with TAAD and patent ductus arteriosus (PDA) (Pannu et al., 2007). L1264P was identified in three family members with history of PDA, aortic aneurysm/dissection and was absent from 360 control chromosomes (Pannu et al, 2007). The L1264P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts L1264P is probably damaging the protein structure/function. Located in the regulatory region of the MYH11 gene, the presence of L1264P significantly decreases the probability of coiled-coil formation in the normal protein sequence (Pannu et al., 2007). Lastly, the L1264P mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, L1264P in the MYH11 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;D;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.026	D;D;.;D
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		0.98	.;.;.;D
Vest4		0.94
MutPred		0.93		.;.;Loss of MoRF binding (P = 0.0604);Loss of MoRF binding (P = 0.0604);
MVP		0.96
MPC		0.92
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.77

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: rs201831933; hg19: chr16-15820772;