ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4240_4242delinsACG (p.Ala1414Thr)

dbSNP: rs794728676
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254669 SCV000234905 uncertain significance not provided 2020-12-09 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for connective tissue disorder genetic testing at GeneDx, but segregation data is limited or absent at this time A1414T due to either c.4240G>A or c.4240_4242delGCTinsACG are observed in 0.04% (122/277,216) alleles in large population cohorts (Lek et al., 2016) In-frame deletion of an alanine residue and insertion of a threonine residue at position 1414 of the MYH11 gene In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Reported as c.4240G>A or c.4240_4242delGCTinsACG in ClinVar, and classified as a variant of uncertain significance and likely benign variant by other clinical laboratories (ClinVar Variant ID# 201110 and 201073; Landrum et al., 2016)
Ambry Genetics RCV001178104 SCV000319609 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-05-02 criteria provided, single submitter clinical testing The c.4240_4242delGCTinsACG variant (also known as p.A1414T), located in coding exon 30 of the MYH11 gene, results from an in-frame deletion of GCT and insertion of ACG between nucleotide positions 4240 and 4242. This results in the substitution of the alanine residue for a threonine residue at codon 1414, an amino acid with similar properties. This variant (described as c.4261_4263delinsACG p.A1421T) was detected in a whole genome sequencing cohort; however specific clinical details were not provided (Stranneheim H et al. Genome Med, 2021 03;13:40). Based on data from gnomAD, this variant has an overall frequency of approximately 0.04% (121/282870) total alleles studied. The highest observed frequency was approximately 0.07% (96/129186) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001178104 SCV001342459 likely benign Familial thoracic aortic aneurysm and aortic dissection 2020-01-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001178104 SCV002042938 likely benign Familial thoracic aortic aneurysm and aortic dissection 2023-06-13 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003398909 SCV004120224 uncertain significance MYH11-related condition 2022-10-21 criteria provided, single submitter clinical testing The MYH11 c.4261_4263delinsACG variant is predicted to result in an in-frame deletion and insertion. This variant was documented in a rare disease cohort; however, the associated clinical features were not available (Table S7, Stranneheim et al. 2021. PubMed ID: 33726816). In a large population database, this variant may be reported separately as c.4261G>A (p.Ala1421Thr) and c.4263T>G (p.Ala1421=) (https://gnomad.broadinstitute.org/variant/16-15818143-C-T; https://gnomad.broadinstitute.org/variant/16-15818141-A-C), but it can also be reported as a multi-nucleotide variant c.4261_4263delinsACG (p.Ala1421Thr) which is documented in 121 heterozygous individuals (https://gnomad.broadinstitute.org/variant/16-15818141-AGC-CGT). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000254669 SCV004563400 uncertain significance not provided 2023-04-18 criteria provided, single submitter clinical testing The MYH11 c.4240_4242delinsACG; p.Ala1414Thr variant (rs794728676), to our knowledge, is not reported in the medical literature associated with disease but is reported in ClinVar (Variation ID: 201110). This variant is found in the general population with an approximate overall allele frequency of 0.044% (125/282870 alleles, based on the frequency of the c.4240G>A component variant) in the Genome Aggregation Database. Computational analyses are uncertain whether the p.Ala1414Thr variant is neutral or deleterious (REVEL: 0.296). Due to limited information, the clinical significance of the c.4240_4242delinsACG; p.Ala1414Thr variant is uncertain at this time.
Invitae RCV003765124 SCV004672476 likely benign Aortic aneurysm, familial thoracic 4 2019-06-04 criteria provided, single submitter clinical testing

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