Submissions for variant NM_002474.3(MYH11):c.2098C>T (p.Arg700Trp)

gnomAD frequency: 0.00001  dbSNP: rs886038932

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000246855	SCV000319219	uncertain significance	Cardiovascular phenotype	2013-11-21	criteria provided, single submitter	clinical testing	The p.R700W variant (also known as c.2098C>T) is located in coding exon 16 of the MYH11 gene. This alteration results from a C to T substitution at nucleotide position 2098. The arginine at codon 700 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is conserved in available vertebrate species except for one species of fish. 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 variant remains unclear.​
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641599	SCV000763241	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 707 of the MYH11 protein (p.Arg707Trp). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 263807). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health	RCV001179386	SCV001344040	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-02-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 707 of the MYH11 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Wolff-Parkinson-White syndrome (PMID: 32233023). This variant has been identified in 3/282506 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.
GeneDx	RCV001547060	SCV001766682	likely pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Identified in published literature in a patient with Wolff-Parkinson-White syndrome and supraventricular tachycardia who harbored additional cardiogenetic variants (Coban-Akdemir et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2119C>T p.(R707W); This variant is associated with the following publications: (PMID: 36571289, 32233023)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469090	SCV002766124	uncertain significance	not specified	2022-11-27	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.2119C>T (p.Arg707Trp) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 282506 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2119C>T has been reported in the literature in at least one individual affected with Aortopathy with another variant of uncertain significance (Coban-Akdemir_2020). This report does 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. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001179386	SCV004823597	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-04-25	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the myosin motor domain of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on 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 3/276898 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.