Submissions for variant NM_016203.4(PRKAG2):c.425C>T (p.Thr142Ile)

gnomAD frequency: 0.00010  dbSNP: rs397517270

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038939	SCV000062617	uncertain significance	not specified	2010-08-26	criteria provided, single submitter	clinical testing	The Thr142Ile variant has not been reported in the literature. However, this var iant has been identified by our laboratory in one individual with a second, like ly pathogenic mutation and in another individual with a clinical diagnosis of d ilated cardiomyopathy (DCM); PRKAG2 variants are more commonly associated with HCM/LVH and WPW (Oliveira, 2003). In addition, the Thr80Asn variant is located outside the CBS domain region where all pathogenic PRKAG2 variants have been id entified to date. In summary, while these observations suggest that this could be a benign variant, its clinical significance cannot be determined with certain ty at this time.
GeneDx	RCV000656954	SCV000208969	uncertain significance	not provided	2018-04-16	criteria provided, single submitter	clinical testing	The T142I variant has been reported previously in association with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) (Pugh et al., 2014; Miszalski-Jamka et al., 2017; Walsh et al.., 2017). Pugh et al. (2014) reported T142I as a variant of uncertain significance in one patient who was diagnosed with sporadic DCM. Subsequently, T142I was reported in a patient with LVNC who underwent whole exome sequencing (WES) who also harbored a variant in the ABCC6 gene (Miszalski-Jamka et al., 2017). In addition, the T142I variant has been classified as a variant of uncertain significance by several other clinical laboratories in ClinVar (SCV000062617.5; SCV000290210.2; SCV000290210.2; Landrum et al., 2016). The T142I variant is a non-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Lastly, the T142I variant was observed in 0.0197% (2/10152) of alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek et al., 2016).
Invitae	RCV000226771	SCV000290210	likely benign	Lethal congenital glycogen storage disease of heart	2024-01-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000379140	SCV000467645	uncertain significance	Wolff-Parkinson-White pattern	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000284645	SCV000467646	uncertain significance	Hypertrophic cardiomyopathy 6	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000515233	SCV000611505	uncertain significance	Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern	2021-10-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769254	SCV000900630	uncertain significance	Cardiomyopathy	2023-04-04	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000656954	SCV000927505	uncertain significance	not provided	2017-12-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769254	SCV001350803	uncertain significance	Cardiomyopathy	2023-11-14	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 142 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 30847666), left ventricular noncompaction (PMID: 28798025), possible arrhythmogenic right ventricular cardiomyopathy (PMID: 29253866), or long QT syndrome (PMID: 33876311). This variant has also been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 35588295), including one de novo report (PMID: 35588295). This variant has also been identified in 20/282698 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491968	SCV000298152	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2016-05-01	no assertion criteria provided	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415017	SCV000492664	uncertain significance	Hypertrophic cardiomyopathy	2016-01-26	no assertion criteria provided	clinical testing