Submissions for variant NM_002474.3(MYH11):c.4994G>T (p.Arg1665Leu)

gnomAD frequency: 0.00013  dbSNP: rs144813247

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182525	SCV000234872	uncertain significance	not provided	2024-05-21	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559002	SCV000641061	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1672 of the MYH11 protein (p.Arg1672Leu). This variant is present in population databases (rs144813247, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of thoracic aortic aneurysm and dissection (internal data). ClinVar contains an entry for this variant (Variation ID: 201081). 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.
Color Diagnostics, LLC DBA Color Health	RCV001181815	SCV001347046	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 1672 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 cardiovascular disorders in the literature. This variant has been identified in 9/282884 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.
Ambry Genetics	RCV001181815	SCV002643550	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-08-21	criteria provided, single submitter	clinical testing	The p.R1665L variant (also known as c.4994G>T), located in coding exon 34 of the MYH11 gene, results from a G to T substitution at nucleotide position 4994. The arginine at codon 1665 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002503709	SCV002817014	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-10-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182525	SCV000925175	uncertain significance	not provided	2016-12-29	no assertion criteria provided	provider interpretation	Genetic testing looked for variants in 15 genes associated with aneurysms and dissections: ACTA2, COL3A1, FBN1, FBN2, MAT2A, MYH11, MYLK, MYH11, PRKG1, SKI, SLC2A10, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2. Analysis also included deletion/duplication studies using comparative genomic hybridization for all of the genes mentioned above. Results reported on September 29, 2016 show that no disease-causing variants were found. However, a variant of unknown significance was found: See report below. p.Arg1665Leu (c.4994G>T) in the MYH11 gene (NM_002474.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data and presence in the general population we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated cases of FTAAD (not including this patient's family) that is listed in Clinvar with no additional data clinical data. The Arg at codon 1665 is not well conserved across species, and neither are neighboring amino acids. Pufferfish (His), Zebrafish (His), and fruit fly (Lys) all have different amino acids at this position. Other variants have not been reported in association with disease at this codon or in nearby codons. Missense variation has been reported as pathogenic and likely pathogenic in other individuals in clinvar. This variant is not in a known protein domain. There is significant variation at codon 1665 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >126,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. 10 individuals have the same p.Arg1665Leu variant our patient has, 9 individuals have p.Arg1665His, and 12 individuals have p.Arg1665Cys. In total, 29 individuals have variation at this position for a total frequency of 1 in 4344 individuals in the general population which is likely too common for this variant to play a strong role in causing aneurysms and dissections.