Submissions for variant NM_002474.3(MYH11):c.5585G>A (p.Arg1862His) (rs146228576)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182534	SCV000234882	uncertain significance	not provided	2018-05-02	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH11 gene. The R1862H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 127/277052 (0.05%) alleles from individuals of multiple ethnic backgrounds, including 90/10148 (0.9%) Ashkenazi Jewish alleles, in large population cohorts (Lek et al., 2016). The R1862H variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for cardiogenetic testing at GeneDx. So far, segregation data is limited or absent for these individuals. The R1862H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina	RCV000280640	SCV000395200	uncertain significance	Lissencephaly, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV001085094	SCV000543722	benign	Aortic aneurysm, familial thoracic 4	2019-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617240	SCV000739196	uncertain significance	Cardiovascular phenotype	2016-11-30	criteria provided, single submitter	clinical testing	The p.R1862H variant (also known as c.5585G>A), located in coding exon 38 of the MYH11 gene, results from a G to A substitution at nucleotide position 5585. The arginine at codon 1862 is replaced by histidine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of approximately 0.04% (127/282506) total alleles studied. The highest observed frequency was 0.88% (89/10158) of Ashkenazi Jewish alleles. This amino acid position is highly conserved in available vertebrate species. 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.
Color	RCV000776147	SCV000911145	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-04-07	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001085094	SCV001279560	uncertain significance	Aortic aneurysm, familial thoracic 4	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000776147	SCV001333415	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-23	criteria provided, single submitter	clinical testing