Submissions for variant NM_002474.3(MYH11):c.2005C>T (p.Arg669Cys)

gnomAD frequency: 0.00079  dbSNP: rs111404182

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148694	SCV000190421	uncertain significance	Aortic aneurysm, familial thoracic 4	2015-11-01	criteria provided, single submitter	research
GeneDx	RCV000586477	SCV000234842	likely benign	not provided	2021-05-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26332594, 27647783, 25839328, 25637381, 26077850, 22955375, 23142374, 17956658, 27153395, 29543232)
Ambry Genetics	RCV000776190	SCV000318098	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-08-16	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148694	SCV000543735	likely benign	Aortic aneurysm, familial thoracic 4	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505700	SCV000697641	likely benign	not specified	2024-06-26	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.2026C>T (p.Arg676Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251374 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 800 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06).c.2026C>T has been reported in the literature in several individuals without strong evidence for pathogenicity (example: Amendola_2015, Maxwell_2016. In one of these individuals another pathogenic variant (FBN1 c.3012C>A, p.Tyr1004) that could explain the patient phenotype, has been reported further providing supporting evidence for a benign role (Renner_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 161319). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586477	SCV000884173	uncertain significance	not provided	2017-07-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776190	SCV000911319	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-09-13	criteria provided, single submitter	clinical testing	Likely Benign based on current evidence: This missense variant is located in the myosin head/motor domain of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 190/277130 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and is fairly common in the Ashkenazi Jewish population (14/10148 chromosomes; 0.14%) and Non-Finnish European population (126/126640 chromosomes; 0.099%). This variant allele frequency is greater than expected for MYH11-related disorders based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000586477	SCV001150837	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	MYH11: BS1
Illumina Laboratory Services, Illumina	RCV000148694	SCV001280251	uncertain significance	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, 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776190	SCV001334008	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-09-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586477	SCV001808446	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586477	SCV001975910	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917465	SCV004728235	likely benign	MYH11-related disorder	2022-02-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).