rs267606902

chr16-15748092-C-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.2135G>A(p.Arg712Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 7.90

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]

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, 0.984
• PP5: Variant 16-15748092-C-T is Pathogenic according to our data. Variant chr16-15748092-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14135.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.2135G>A	p.Arg712Gln	missense_variant	17/41	ENST00000300036.6
MYH11	NM_001040113.2	c.2156G>A	p.Arg719Gln	missense_variant	18/43	ENST00000452625.7
MYH11	NM_001040114.2	c.2156G>A	p.Arg719Gln	missense_variant	18/42
MYH11	NM_022844.3	c.2135G>A	p.Arg712Gln	missense_variant	17/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.2135G>A	p.Arg712Gln	missense_variant	17/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.2156G>A	p.Arg719Gln	missense_variant	18/43	1	NM_001040113.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 09, 2024	The p.R712Q pathogenic mutation (also known as c.2135G>A), located in coding exon 16 of the MYH11 gene, results from a G to A substitution at nucleotide position 2135. The arginine at codon 712 is replaced by glutamine, an amino acid with some similar properties. In one study, this mutation segregated with thoracic aortic aneurysms and dissections (TAAD) and/or patent ductus arteriosus (PDA) phenotypes in five individuals in one family, and was not present in 360 control chromosomes (Pannu H et al. Hum Mol Genet. 2007;16(20):2453-62). This alteration has been observed in at least one additional individual with a personal and/or family history of TAAD (Ambry internal data). 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 alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Feb 27, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 07, 2023	The c.2156G>A (p.Arg719Gln) variant of the MYH11 gene has been reported to segregate with thoracic aortic aneurysms and dissections (TAAD) and/or patent ductus arteriosus (PDA) phenotype in one family without being observed in 360 control chromosomes (PMID: 17666408). In this family, five individuals with this variant were affected with TADD, PDA, or premature CAD, while three other individuals with this variant had no phenotype, suggesting incomplete penetrance. This variant was also observed in an unrelated Japanese individual with PDA/TAAD (PMID: 30885847), in a French study of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD) (classified as a variant of unknown clinical significance, PMID: 30739908), and in an individual with aortic dissection (AD) (classified as likely pathogenic, PMID: 33083483). This variant is predicted to affect the ATPase region and destabilize the SH1 helix and hence prevent the motor domain and lever arm from communicating effectively (PMID: 17666408). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Computational evidence supports a deleterious effect on the gene or gene product. Therefore, the c.2156G>A (p.Arg719Gln) variant of the MYH11 gene is classified as likely pathogenic. -

Aortic aneurysm, familial thoracic 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 05, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 14135). This variant is also known as p.Arg712Gln. This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 17666408, 30885847; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 719 of the MYH11 protein (p.Arg719Gln). -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27879251, 30885847, 33083483, 34350653, 17666408) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2019	- -

Aortic aneurysm, familial thoracic 4;C5543466:Visceral myopathy 2;C5543476:Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.91
MutPred		0.97		.;.;Loss of catalytic residue at R712 (P = 0.0524);Loss of catalytic residue at R712 (P = 0.0524);
MVP		0.95
MPC		2.0
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.80
gMVP		0.83

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: rs267606902; hg19: chr16-15841949; COSMIC: COSV55543102; COSMIC: COSV55543102;