Submissions for variant NM_002474.3(MYH11):c.3340C>T (p.Arg1114Trp)

gnomAD frequency: 0.00002  dbSNP: rs202004234

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182505	SCV000234851	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226763	SCV000285785	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-11-27	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 1121 of the MYH11 protein (p.Arg1121Trp). This variant is present in population databases (rs202004234, gnomAD 0.004%). 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: 201062). 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 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000226763	SCV000896507	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000778041	SCV000914155	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1121 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 not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 3/251484 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.
Illumina Laboratory Services, Illumina	RCV000226763	SCV001274747	uncertain significance	Aortic aneurysm, familial thoracic 4	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000182505	SCV002501804	uncertain significance	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002287384	SCV002577843	uncertain significance	See cases	2021-12-17	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3,BP1
Ambry Genetics	RCV000778041	SCV002606638	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-02-10	criteria provided, single submitter	clinical testing	The p.R1114W variant (also known as c.3340C>T), located in coding exon 25 of the MYH11 gene, results from a C to T substitution at nucleotide position 3340. The arginine at codon 1114 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000778041	SCV004821339	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-11	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the coiled coil myosin tail 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 5/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.