Submissions for variant NM_002474.3(MYH11):c.3949C>A (p.Leu1317Ile)

gnomAD frequency: 0.00600  dbSNP: rs141159831

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182472	SCV000234817	benign	not specified	2014-06-17	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.
PreventionGenetics, part of Exact Sciences	RCV000182472	SCV000306185	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241941	SCV000317887	benign	Familial thoracic aortic aneurysm and aortic dissection	2014-10-06	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001000699	SCV000395292	likely benign	Aortic aneurysm, familial thoracic 4	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000336390	SCV000395293	uncertain significance	Lissencephaly, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001000699	SCV000556136	benign	Aortic aneurysm, familial thoracic 4	2024-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000241941	SCV000901075	benign	Familial thoracic aortic aneurysm and aortic dissection	2022-07-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000241941	SCV000913753	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812173	SCV001157738	likely benign	not provided	2021-11-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121349	SCV001279943	benign	Lissencephaly 4	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182472	SCV001362300	benign	not specified	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.3970C>A (p.Leu1324Ile) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 276966 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1464 fold of 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. To our knowledge, no occurrence of c.3970C>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.