Submissions for variant NM_053025.4(MYLK):c.2461C>T (p.Arg821Trp)

gnomAD frequency: 0.00018  dbSNP: rs150007422

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000549158	SCV000440316	uncertain significance	Aortic aneurysm, familial thoracic 7	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549158	SCV000650526	uncertain significance	Aortic aneurysm, familial thoracic 7	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 821 of the MYLK protein (p.Arg821Trp). This variant is present in population databases (rs150007422, gnomAD 0.03%). This missense change has been observed in individual(s) with hereditary thoracic aortic disease (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 342890). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001580019	SCV002098209	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	Reported in two individuals from a Dutch cohort of patients evaluated for heritable thoracic aortic disorders; a seven year old with pulmonary embolism and prominent venous pattern, and an adult with a history of aortic aneurysms and an atrial septal defect (PMID: 29907982); Identified in a patient with Marfan syndrome in published literature (PMID: 30675029); this patient harbored additional cardiogenetic variants (PMID: 30675029); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29907982, 30675029)
Ambry Genetics	RCV002450914	SCV002736056	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-14	criteria provided, single submitter	clinical testing	The p.R821W variant (also known as c.2461C>T), located in coding exon 14 of the MYLK gene, results from a C to T substitution at nucleotide position 2461. The arginine at codon 821 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in thoracic aortic aneurysm and dissection (TAAD) cohorts; however, clinical details were limited and/or co-occurring variants in other TAAD-related genes were detected (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; Renner S et al. Genet Med. 2019 Aug;21(8):1832-1841). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002488740	SCV002797620	uncertain significance	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2021-08-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001580019	SCV005875512	uncertain significance	not provided	2024-06-03	criteria provided, single submitter	clinical testing	The MYLK c.2461C>T; p.Arg821Trp variant (rs150007422, ClinVar Variation ID: 342890) is reported in the literature in individuals with suspected heritable thoracic aortic disease; however, disease association is unclear (Overwater 2018, Renner 2019). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (43/129,124 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.188). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Overwater E et al. Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat. 2018 Sep;39(9):1173-1192. PMID: 29907982. Renner S et al. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. Genet Med. 2019 Aug;21(8):1832-1841. PMID: 30675029.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001580019	SCV001809405	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001580019	SCV001953770	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001580019	SCV001974662	uncertain significance	not provided		no assertion criteria provided	clinical testing