Submissions for variant NM_002474.3(MYH11):c.5566C>T (p.Leu1856=)

gnomAD frequency: 0.00150  dbSNP: rs142639688

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000126967	SCV000170498	benign	not specified	2013-10-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000242448	SCV000319215	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2015-03-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000242448	SCV000395201	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000371604	SCV000395202	uncertain significance	Lissencephaly, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000464298	SCV000556091	benign	Aortic aneurysm, familial thoracic 4	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001092817	SCV000604338	benign	not provided	2023-10-16	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000464298	SCV000745472	likely benign	Aortic aneurysm, familial thoracic 4	2017-06-28	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680549	SCV000807960	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000242448	SCV000902158	benign	Familial thoracic aortic aneurysm and aortic dissection	2016-08-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000242448	SCV000911314	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000126967	SCV000917828	benign	not specified	2018-05-14	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.5587C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 277156 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 1048-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. The variant, c.5587C>T, has been reported in the literature in one individual affected with Aortopathy (van de Luijtgaarden_2015). 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001092817	SCV001249510	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MYH11: BP4, BP7
Illumina Laboratory Services, Illumina	RCV000464298	SCV001279561	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000464298	SCV000745953	likely benign	Aortic aneurysm, familial thoracic 4	2014-11-19	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001092817	SCV001926941	likely benign	not provided		no assertion criteria provided	clinical testing