Submissions for variant NM_033118.4(MYLK2):c.1253C>T (p.Thr418Ile)

gnomAD frequency: 0.00048  dbSNP: rs144129296

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526748	SCV000652377	likely benign	Hypertrophic cardiomyopathy 1	2025-01-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255493	SCV001431920	likely benign	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: MYLK2 c.1253C>T (p.Thr418Ile) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251340 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 56 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1253C>T in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported ( TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role (internal database). One ClinVar submitter (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507980	SCV001713849	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001507980	SCV002014012	uncertain significance	not provided	2024-11-06	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
Ambry Genetics	RCV001255493	SCV003971103	uncertain significance	not specified	2023-03-20	criteria provided, single submitter	clinical testing	The c.1253C>T (p.T418I) alteration is located in exon 9 (coding exon 8) of the MYLK2 gene. This alteration results from a C to T substitution at nucleotide position 1253, causing the threonine (T) at amino acid position 418 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003962574	SCV004777465	likely benign	MYLK2-related disorder	2022-06-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).