Submissions for variant NM_002474.3(MYH11):c.4240G>A (p.Ala1414Thr)

gnomAD frequency: 0.00051  dbSNP: rs112467954

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182517	SCV000234863	uncertain significance	not provided	2018-10-17	criteria provided, single submitter	clinical testing	Although the A1414T variant of uncertain significance in the MYH11 gene has not been published as a pathogenic variant or as a benign variant to our knowledge, this variant has been identified, both independently and/or in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The A1414T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, this variant is observed in 94/126710 (0.07%) European (non-Finnish) alleles and 20/34420 (0.06%) Latino alleles in large population cohorts (Lek et al., 2016).
Ambry Genetics	RCV001171276	SCV000317328	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-05-14	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659918	SCV000781822	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780512	SCV000917826	benign	not specified	2022-05-09	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.4261G>A (p.Ala1421Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) 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 0.00044 in 282870 control chromosomes (gnomAD), predominantly at a frequency of 0.00074 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 592 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.4261G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001080924	SCV001274383	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.
Illumina Laboratory Services, Illumina	RCV001116325	SCV001274384	uncertain significance	Lissencephaly 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171276	SCV001333985	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-06-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182517	SCV002049018	uncertain significance	not provided	2023-04-18	criteria provided, single submitter	clinical testing	The MYH11 c.4240G>A p.Ala1414Thr variant (rs112467954), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 201073). This variant is found in the general population with an overall allele frequency of 0.04% (125/282,870 alleles) in the Genome Aggregation Database. The Alanine at codon 1414 is moderately conserved, but computational analyses predict that this variant is uncertain (REVEL: 0.296). Due to limited information, the clinical significance of the MYH11 p.Ala1414Thr variant is uncertain at this time.
CeGaT Center for Human Genetics Tuebingen	RCV000182517	SCV003917489	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MYH11: BP4
PreventionGenetics, part of Exact Sciences	RCV003907637	SCV004725658	likely benign	MYH11-related disorder	2022-11-02	criteria provided, single submitter	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).