Submissions for variant NM_002474.3(MYH11):c.4861A>C (p.Lys1621Gln)

gnomAD frequency: 0.00011  dbSNP: rs34321232

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182562	SCV000052967	uncertain significance	not specified	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.4882A>C (p.Lys1628Gln) results in a conservative amino acid change located in the Myosin tail domain 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 9.9e-05 in 251470 control chromosomes. The observed variant frequency is approximately 79.5- fold the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. c.4882A>C has been reported in the literature in individuals affected with aneurysm and thoracic aortic disease (examples- Weerakkody_2018, Overwater_2018). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV000762209	SCV000234912	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(K1628Q); This variant is associated with the following publications: (PMID: 29907982, 32238909, 20226094, 29543232, 35393538, 35276540)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554857	SCV000641058	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1628 of the MYH11 protein (p.Lys1628Gln). This variant is present in population databases (rs34321232, gnomAD 0.02%). This missense change has been observed in individual(s) with aortic aneurysm (PMID: 29543232, 29907982). ClinVar contains an entry for this variant (Variation ID: 36622). 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. 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.
Ambry Genetics	RCV000611869	SCV000739203	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-31	criteria provided, single submitter	clinical testing	The p.K1621Q variant (also known as c.4861A>C), located in coding exon 33 of the MYH11 gene, results from an A to C substitution at nucleotide position 4861. The lysine at codon 1621 is replaced by glutamine, an amino acid with similar properties, and is located in the coiled coil domain. This variant was detected in an individual with a thoracic aortic aneurysm (TAAD) and no known family history of the condition; however, clinical details were limited (Weerakkody R et al. Genet. Med., 2018 Nov;20:1414-1422). This alteration was also reported in a sudden unexplained death cohort (Neubauer J et al. Forensic Sci Int, 2022 May;334:111240). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000554857	SCV000744016	uncertain significance	Aortic aneurysm, familial thoracic 4	2016-02-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000554857	SCV000745958	uncertain significance	Aortic aneurysm, familial thoracic 4	2017-02-16	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659924	SCV000781828	uncertain significance	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762209	SCV000892483	uncertain significance	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000762209	SCV000987635	uncertain significance	not provided		criteria provided, single submitter	clinical testing
Mendelics	RCV000554857	SCV001139961	uncertain significance	Aortic aneurysm, familial thoracic 4	2019-05-28	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000554857	SCV001160810	uncertain significance	Aortic aneurysm, familial thoracic 4	2019-12-11	criteria provided, single submitter	research	ACMG evidence PP2, PP3, PP5
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000611869	SCV001333418	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-02-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000611869	SCV001354763	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. Computational prediction suggests that this variant may have a 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 two unrelated individuals affected with thoracic aortic aneurysm (PMID: 29907982, 29543232), in an individual affected with sudden unexplained death (PMID: 35276540), and in another individual affected with atrioventricular septal defect (PMID: 35393538). This variant has been identified in 29/282846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482921	SCV002780792	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-10-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000762209	SCV003817183	uncertain significance	not provided	2022-01-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000611869	SCV004821166	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. 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 two unrelated individuals affected with thoracic aortic aneurysm (PMID: 29907982, 29543232), in an individual affected with sudden unexplained death (PMID: 35276540), and in another individual affected with atrioventricular septal defect (PMID: 35393538). This variant has also been identified in 29/282846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000611869	SCV000731234	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000762209	SCV001550154	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH11 p.K1621Q variant was identified in an individual with thoracic aortic aneurysm/aortic dissection and an individual with suspected hereditary thoracic aortic disease (Weerakkody_2018_ PMID: 29543232; Overwater_2018_ PMID: 29907982). This variant was also identified in an individual with generalized epilepsy inherited from a presumably unaffected father without a family history of epilepsy (Benson_2020_PMID: 32238909). The variant was identified in dbSNP (ID: rs34321232) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and ten other submitters; and as likely pathogenic by Centre for Genomic and Experimental Medicine, University of Edinburgh). The variant was identified in control databases in 29 of 282846 chromosomes at a frequency of 0.0001025, and was observed at the highest frequency in the European (non-Finnish) population in 27 of 129166 chromosomes (freq: 0.0002090) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.K1621 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762209	SCV001973996	uncertain significance	not provided		no assertion criteria provided	clinical testing