Submissions for variant NM_002474.3(MYH11):c.3874G>A (p.Val1292Ile)

dbSNP: rs151058774

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659916	SCV000781820	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701003	SCV000829783	uncertain significance	Aortic aneurysm, familial thoracic 4	2022-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1299 of the MYH11 protein (p.Val1299Ile). This variant is present in population databases (rs151058774, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MYH11-related conditions (PMID: 32368696; Invitae). ClinVar contains an entry for this variant (Variation ID: 547546). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000762211	SCV000892485	uncertain significance	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000773634	SCV000907328	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1299 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 been reported in an individual affected with sporadic congenital heart disease with left ventricular outflow tract obstruction (PMID: 32368696). This variant has been identified in 11/282562 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	RCV000762211	SCV001788660	uncertain significance	not provided	2021-06-24	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 does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance and as a likely benign variant (ClinVar Variant ID# 547546; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533)
All of Us Research Program, National Institutes of Health	RCV000773634	SCV004821286	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1299 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 been reported in an individual affected with sporadic congenital heart disease with left ventricular outflow tract obstruction (PMID: 32368696). This variant has been identified in 11/282562 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	RCV000773634	SCV005018983	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-12	criteria provided, single submitter	clinical testing	The p.V1292I variant (also known as c.3874G>A), located in coding exon 28 of the MYH11 gene, results from a G to A substitution at nucleotide position 3874. The valine at codon 1292 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a congenital heart disease cohort (Edwards JJ et al. JACC Basic Transl Sci, 2020 Apr;5:376-386). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.