Submissions for variant NM_053025.4(MYLK):c.3637G>C (p.Val1213Leu)

dbSNP: rs368390254

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688896	SCV000816523	uncertain significance	Aortic aneurysm, familial thoracic 7	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1213 of the MYLK protein (p.Val1213Leu). This variant is present in population databases (rs368390254, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 568511). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 80%. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000688896	SCV000898842	uncertain significance	Aortic aneurysm, familial thoracic 7	2018-09-17	criteria provided, single submitter	clinical testing	MYLK NM_053025.3 exon 20 p.Val1213Leu (c.3637G>C): This variant has not been reported in the literature and is present in 0.01% (11/116464) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-123401086-C-T). This variant amino acid Leucine (Leu) is present in 2 species (chinese hamster and golden hamster), and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Of note, another variant at the same amino acid residue position (p.Val1213Met) has been reported as being possibly associated with aortic dissections in a single individual (Wang et al. PMID: 21055718). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Phosphorus, Inc.	RCV001823743	SCV002073413	uncertain significance	not specified	2022-01-13	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of valine with leucine at codon 1213 of the MYLK gene. The variant has an entry in ClinVar (568511) NM_053025.4 (MYLK): c.3637G>C (p.Val1213Leu) and has occurred in GnomAD with a total MAF of 0.0040% and highest MAF of 0.0089% in the European population. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it benign, and SIFT tolerated, but no functional studies were performed to confirm this prediction. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002458214	SCV002614188	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-16	criteria provided, single submitter	clinical testing	The p.V1213L variant (also known as c.3637G>C), located in coding exon 17 of the MYLK gene, results from a G to C substitution at nucleotide position 3637. The valine at codon 1213 is replaced by leucine, an amino acid with highly similar properties. In addition, a different alteration at the same position, p.V1213M, has been detected in an individual with familial thoracic aortic aneurysm and dissection (TAAD) (Wang L et al. Am. J. Hum. Genet., 2010 Nov;87:701-7). This amino acid position is highly 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.
GeneDx	RCV001579632	SCV002770396	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002493164	SCV002788579	uncertain significance	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2021-10-28	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002493164	SCV003920252	uncertain significance	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2021-03-30	criteria provided, single submitter	clinical testing	MYLK NM_053025.3 exon 20 p.Val1213Leu (c.3637G>C): This variant has not been reported in the literature and is present in 0.01% (11/116464) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-123401086-C-T). This variant is present in ClinVar (Variation ID:568511). This variant amino acid Leucine (Leu) is present in 2 species (chinese hamster and golden hamster), and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Of note, another variant at the same amino acid residue position (p.Val1213Met) has been reported as being possibly associated with aortic dissections in three individuals (Wang 2010 PMID: 21055718, Weerakkody 2018 PMID:29543232). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001823743	SCV004099731	uncertain significance	not specified	2024-09-11	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.3637G>C (p.Val1213Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 229728 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYLK causing Megacystis-Microcolon Hypoperistalsis Syndrome 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3637G>C in individuals affected with Megacystis-Microcolon Hypoperistalsis Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 568511). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579632	SCV001807951	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579632	SCV001926284	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579632	SCV001972184	likely benign	not provided		no assertion criteria provided	clinical testing