ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.4565T>C (p.Val1522Ala)

gnomAD frequency: 0.00006  dbSNP: rs763880352
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467332 SCV000550007 likely pathogenic Aortic aneurysm, familial thoracic 7 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1522 of the MYLK protein (p.Val1522Ala). This variant is present in population databases (rs763880352, gnomAD 0.009%). This missense change has been observed in individuals with aortic aneurysm (PMID: 29907982; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 409680). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYLK protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000770616 SCV000739287 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-04-20 criteria provided, single submitter clinical testing The p.V1522A variant (also known as c.4565T>C), located in coding exon 24 of the MYLK gene, results from a T to C substitution at nucleotide position 4565. The valine at codon 1522 is replaced by alanine, an amino acid with similar properties. This alteration was detected in a cohort of individuals with familial or early onset aortic aneurysms/dissections or signs of generalized connective tissue disorders. Authors noted that it segregated with disease in at least one family member; however, no specific details were provided (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756399 SCV000884199 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing The MYLK c.4565T>C; p.Val1522Ala variant (rs763880352), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% (identified on 12 out of 277,196 chromosomes) and is classified as a variant of uncertain significance in ClinVar (ID: 409680). The valine at position 1522 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Val1522Ala variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Val1522Ala variant cannot be determined with certainty.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770616 SCV000902067 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000756399 SCV001764211 uncertain significance not provided 2023-03-09 criteria provided, single submitter clinical testing Reported in a 62-year-old Dutch male with aneurysms of the aortic root and ascending aorta, right bundle branch block, and skeletal features suggestive of a connective tissue disorder; this variant was also present in his similarly affected brother (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907982, 26582918)
Preventiongenetics, part of Exact Sciences RCV003401479 SCV004105802 uncertain significance MYLK-related condition 2023-04-14 criteria provided, single submitter clinical testing The MYLK c.4565T>C variant is predicted to result in the amino acid substitution p.Val1522Ala. This variant was reported in an individual with a suspected heritable thoracic aortic disorder (Table S1, Patient ID 122, Overwater et al. 2018. PubMed ID: 29907982). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-123366125-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000756399 SCV001809047 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000756399 SCV001930757 uncertain significance not provided no assertion criteria provided clinical testing

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