ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4240G>A (p.Ala1414Thr) (rs112467954)

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Total submissions: 8
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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 RCV000252216 SCV000317328 likely benign Cardiovascular phenotype 2018-05-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV001080924 SCV000543720 likely benign Aortic aneurysm, familial thoracic 4 2019-12-23 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659918 SCV000781822 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780512 SCV000917826 likely benign not specified 2017-10-02 criteria provided, single submitter clinical testing Variant summary: The MYH11 c.4261G>A (p.Ala1421Thr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Myosin tail(IPR002928) (InterPro). 2/4 in silico tools predict a benign outcome for this variant. The variant was found in the control population dataset of gnomAD in 122/277216 control chromosomes at a frequency of 0.0004401, which is approximately 352 times the estimated maximal expected allele frequency of a pathogenic MYH11 variant (0.0000013), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic labs have classified the variant as a VUS. Taken together, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 2019-04-25 criteria provided, single submitter clinical testing

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