Submissions for variant NM_016203.4(PRKAG2):c.1318C>T (p.His440Tyr)

gnomAD frequency: 0.00051  dbSNP: rs201878539

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038915	SCV000062593	likely benign	not specified	2015-05-20	criteria provided, single submitter	clinical testing	p.His440Tyr in exon 12 of PRKAG2: This variant is not expected to have clinical significance due to its frequency in the general population and lack of evolutio nary conservation of the affected amino acid. It has been identified in 0.2% (20 /10406) of African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs201878539) and 3 mammals (guinea pig, rabbit, and aardvark) have a tyrosine (Tyr) at this position despite high nearby amino a cid conservation, suggesting that this change may be tolerated.
GeneDx	RCV000038915	SCV000208954	likely benign	not specified	2017-12-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000724478	SCV000225670	uncertain significance	not provided	2014-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081726	SCV000561815	likely benign	Lethal congenital glycogen storage disease of heart	2025-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621627	SCV000740112	likely benign	Cardiovascular phenotype	2019-03-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001178107	SCV001342463	likely benign	Cardiomyopathy	2018-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038915	SCV001363080	likely benign	not specified	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: PRKAG2 c.1318C>T (p.His440Tyr) results in a conservative amino acid change located in the CBS domain (IPR000644) of 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 0.00018 in 282880 control chromosomes, predominantly at a frequency of 0.0017 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 68 fold the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1318C>T has been reported in the literature in an individual affected with dilated Cardiomyopathy (Pugh_2014). This report however, does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724478	SCV002047746	likely benign	not provided	2021-11-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534819	SCV004721343	likely benign	PRKAG2-related disorder	2022-01-27	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).