16-15718337-C-T

Variant names:

• chr16-15718337-C-T
• rs142546324
• NM_002474.3:c.5273G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM5 PP3_Moderate BS1_Supporting

The NM_002474.3(MYH11):​c.5273G>A​(p.Arg1758Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,609,078 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1758W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:10 B:1
• Conservation: PhyloP100: 7.67

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]

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 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-15718338-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000184 (28/152166) while in subpopulation NFE AF= 0.000353 (24/68020). AF 95% confidence interval is 0.000243. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH11	NM_002474.3	c.5273G>A	p.Arg1758Gln	missense_variant	Exon 37 of 41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.5294G>A	p.Arg1765Gln	missense_variant	Exon 38 of 43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.948-5854C>T		intron_variant	Intron 8 of 8	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.5273G>A	p.Arg1758Gln	missense_variant	Exon 37 of 41	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.5294G>A	p.Arg1765Gln	missense_variant	Exon 38 of 43	1	NM_001040113.2	ENSP00000407821.2
NDE1	ENST00000396354.6	c.948-5854C>T		intron_variant	Intron 8 of 8	1	NM_017668.3	ENSP00000379642.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000174 AC: 43 AN: 247716 Hom.: 0 AF XY: 0.000171 AC XY: 23 AN XY: 134238

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1456912 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 146 AN XY: 724904

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74334

Gnomad4 AFR AF: 0.0000965

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: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:10 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:3

-

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 06, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1758Q variant (also known as c.5273G>A), located in coding exon 36 of the MYH11 gene, results from a G to A substitution at nucleotide position 5273. The arginine at codon 1758 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD) as well as in asymptomatic individuals, including in a large family where this alteration segregated with disease apparently in cis with an MYH11 splice site variant (c.4578+1G>T, reported as IVS32+1G>T) (Zhu L et al. Nat. Genet., 2006 Mar;38:343-9; Weerakkody R et al. Genet. Med., 2018 11;20:1414-1422; Poninska JK et al. J Transl Med, 2016 05;14:115). This variant has also been reported in an infant and an adult with cerebral aneurysms (Ravindra VM et al. J Neurosurg Pediatr, 2016 Oct;18:463-470; Strzelczyk J et al. Pol Arch Intern Med. 2023 Mar;133(3)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jan 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 1765 of the MYH11 protein. This variant is also known as c.5273G>A, Arg1758Gln based on a different transcript NM_002474.3. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with thoracic aortic aneurysm and dissection and patent ductus arteriosus. The variant was in cis with another canonical splice variant in the same gene that could explain the observed phenotype in this family (PMID: 16444274). This variant has also been reported in an individual affected with thoracic aortic aneurysm as well as in an unaffected family member (PMID: 27146836). This variant has been identified in 55/279074 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:4

Nov 26, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with TAAD; however, all affected members from one large family with this variant were also found to harbor another pathogenic variant on the same allele (in cis) (PMID: 16444274, 27146836, 29543232); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as G5361>A; This variant is associated with the following publications: (PMID: 25637381, 25407000, 22955375, 18400036, 27367753, 29543232, 31389005, 32081817, 28659821, 27146836, 16444274, 36763073, 37937776) -

Sep 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH11 c.5273G>A; p.Arg1758Gln variant (rs142546324) is reported in the literature in several individuals affected with thoracic aortic aneurysm and/or dissection (TAAD) (Poninska 2016, Weerakkody 2018, Zhu 2006) and an individual with cerebral aneurysm (Ravindra 2016). In one family, this variant segregated with the phenotype; however, it also occurred in cis with a splice variant that may have explained their disease (Zhu 2006). The p.Arg1758Gln variant is found in the non-Finnish European population with an allele frequency of 0.04% (52/128,864 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.864). However, due to limited and conflicting information, the significance of this variant is uncertain at this time. References: Poninska JK et al. Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. J Transl Med. 2016 May 4;14(1):115. PMID: 27146836. Ravindra VM et al. Rapid de novo aneurysm formation after clipping of a ruptured middle cerebral artery aneurysm in an infant with an MYH11 mutation. J Neurosurg Pediatr. 2016 Oct;18(4):463-470. PMID: 27367753. Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232. Zhu L et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006 Mar;38(3):343-9. PMID: 16444274. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1765Gln variant in MYH11 has been reported in 4 individuals with thoracic aortic aneurysms and dissection (TAAD) as well as one individual with aneurysm and one with bicuspid aortic valve (Zhu 2006 PMID: 16444274, Poninska 2016 PMID: 27146836, Ravindra 2016 PMID: 27367753, Gillis 2017 PMID: 28659821, Weerakkody 2018 PMID: 29543232). Of note, in one family the p.Arg1765Gln MYH11 variant was identified in cis with a canonical splice variant in all affected individuals (Zhu 2006 PMID: 16444274). It has also been identified in 0.04% (52/128864) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1. -

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

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1765 of the MYH11 protein (p.Arg1765Gln). This variant is present in population databases (rs142546324, gnomAD 0.04%). This missense change has been observed in individual(s) with thoracic aortic aneurysms and dissections (TAAD) (PMID: 16444274, 27146836, 28659821). This variant is also known as p.Arg1758Gln. ClinVar contains an entry for this variant (Variation ID: 161316). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. 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. -

not specified Uncertain:1

Aug 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH11 c.5294G>A (p.Arg1765Gln) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 247716 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5294G>A has been reported in the literature in individuals with different cardiac conditions (Zhu_2006, Poninska_2016, Ravindra_2016, Gillis_2017, Weerakkody_2018), however without strong evidence for causality (e.g., lack of co-segregation data or presence of a different co-occurring pathogenic MYH11 variant). These reports therefore do not provide unequivocal conclusions about association of the variant with Aortopathy. Co-occurrence with a pathogenic variant has been reported (MYH11 c.4578+1G>T, Zhu_2006), providing supporting evidence for a benign role. To our knowledge, this variant has not been reported in any individuals affected with Megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28659821, 37937776, 27146836, 27367753, 29543232, 16444274). ClinVar contains an entry for this variant (Variation ID: 161316). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

MYH11-related disorder Uncertain:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYH11 c.5294G>A variant is predicted to result in the amino acid substitution p.Arg1765Gln. This variant, also known as c.5273G>A (p.Arg1758Gln) in the literature, was reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD; Weerakkody et al. 2018. PubMed ID: 29543232) and in an infant with cerebral artery aneurysm (Ravindra et al. 2016. PubMed ID: 27367753). However, this variant was reported to be in cis with a canonical splice variant in MYH11 in one family segregating with TAAD (Zhu et al. 2006. PubMed ID: 16444274). This variant was documented in an individual with TAAD but also in the individual's unaffected daughter (Poninska et al. 2016. PubMed ID: 27146836). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.8	.;.;M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D;.;D
REVEL	Pathogenic	0.86
Sift	Benign	0.034	D;D;.;D
Sift4G	Uncertain	0.034	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.88
MVP		0.87
MPC		0.77
ClinPred		0.49	T
GERP RS		4.7
Varity_R		0.31
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs142546324; hg19: chr16-15812194; COSMIC: COSV55556203; COSMIC: COSV55556203;