Submissions for variant NM_033118.4(MYLK2):c.173C>A (p.Ala58Asp)

gnomAD frequency: 0.00070  dbSNP: rs138130914

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172570	SCV000051017	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039784	SCV000063473	likely benign	not specified	2015-02-18	criteria provided, single submitter	clinical testing	p.Ala58Asp in exon 3 of MYLK2: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (150/16508) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138130914).
GeneDx	RCV000172570	SCV000236020	benign	not provided	2019-03-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081175	SCV000291169	benign	Hypertrophic cardiomyopathy 1	2024-01-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770567	SCV000902016	benign	Cardiomyopathy	2018-06-28	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000770567	SCV000995695	likely benign	Cardiomyopathy	2017-04-04	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293152	SCV001434142	likely benign	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039784	SCV001448539	benign	not specified	2020-11-17	criteria provided, single submitter	clinical testing	Variant summary: MYLK2 c.173C>A (p.Ala58Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 250664 control chromosomes, predominantly at a frequency of 0.0097 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 390 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 South Asian origin. To our knowledge, no occurrence of c.173C>A in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000039784	SCV000280391	uncertain significance	not specified	2014-10-15	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172570	SCV001743448	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172570	SCV001966817	likely benign	not provided		no assertion criteria provided	clinical testing