Submissions for variant NM_002474.3(MYH11):c.161A>G (p.Lys54Arg)

gnomAD frequency: 0.00001  dbSNP: rs1015353331

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000772796	SCV000906178	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 54 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 1/251406 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001280976	SCV001468357	uncertain significance	Aortic aneurysm, familial thoracic 4	2020-07-17	criteria provided, single submitter	clinical testing	MYH11 NM_002474.2 exon 2 p.Lys54Arg (c.161A>G): This variant has been reported in the literature in one individual with suspected hereditary thoracic aortic disease (Overwater 2018 PMID:29907982). This variant is present in 0.0008% (1/113690) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15931949-T-C) and is present in ClinVar (Variation ID:628339). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001280976	SCV002217912	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 54 of the MYH11 protein (p.Lys54Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of MYH11-related conditions (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 628339). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224466	SCV003920235	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-03-30	criteria provided, single submitter	clinical testing	MYH11 NM_002474.2 exon 2 p.Lys54Arg (c.161A>G): This variant has been reported in the literature in one individual with suspected hereditary thoracic aortic disease (Overwater 2018 PMID:29907982). This variant is present in 0.0008% (1/113690) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-15931949-T-C) and is present in ClinVar (Variation ID:628339). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV000772796	SCV004816890	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-01	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the N-terminal SH3-like domain of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/246172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.