Submissions for variant NM_053025.4(MYLK):c.2474C>T (p.Pro825Leu)

gnomAD frequency: 0.00012  dbSNP: rs201332554

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001170124	SCV000320236	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-12-04	criteria provided, single submitter	clinical testing	The c.2474C>T (p.P825L) alteration is located in exon 18 (coding exon 15) of the MYLK gene. This alteration results from a C to T substitution at nucleotide position 2474, causing the proline (P) at amino acid position 825 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000658971	SCV000536174	uncertain significance	not provided	2025-01-23	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 has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467595	SCV000550027	uncertain significance	Aortic aneurysm, familial thoracic 7	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 825 of the MYLK protein (p.Pro825Leu). This variant is present in population databases (rs201332554, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MYLK-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 264351). 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) performed at Invitae 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.
CeGaT Center for Human Genetics Tuebingen	RCV000658971	SCV000780774	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MYLK: BP4
Fulgent Genetics, Fulgent Genetics	RCV000467595	SCV000897060	uncertain significance	Aortic aneurysm, familial thoracic 7	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170124	SCV001332665	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-01-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000658971	SCV001713301	uncertain significance	not provided	2020-05-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479086	SCV004222988	uncertain significance	not specified	2024-09-11	criteria provided, single submitter	clinical testing	Variant summary: MYLK c.2474C>T (p.Pro825Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 239366 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.2474C>T 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: 264351). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000581201	SCV000692255	uncertain significance	Marfan syndrome	2016-11-09	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000658971	SCV001743205	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658971	SCV001963870	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV002508930	SCV002818344	not provided	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 09-14-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.