Submissions for variant NM_016203.4(PRKAG2):c.1148A>G (p.His383Arg)

dbSNP: rs121908988

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603714	SCV000710840	uncertain significance	not specified	2016-04-15	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.His383Arg variant in PRKAG2 has been reported in 1 individual with HCM and conduction abn ormalities, segregated with disease in 2 affected relatives (Blair 2001), and wa s absent from large population studies. In vitro functional studies provide some evidence that the p.His383Arg variant may impact protein function (Scott 2004). However, these types of assays may not accurately represent biological function . Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is so me suspicion for a pathogenic role, the clinical significance of the p.His383Arg variant is uncertain.
GeneDx	RCV001753407	SCV001985381	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Published in vitro functional study suggests this variant may affect protein function (Scott et al., 2004), although it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28431061, 17667862, 15877279, 11748095, 32646569, 32259713, 11371514, 14722619)
Invitae	RCV002512868	SCV003440629	pathogenic	Lethal congenital glycogen storage disease of heart	2023-02-16	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 14722619). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 383 of the PRKAG2 protein (p.His383Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PRKAG2-related conditions (PMID: 11371514, 32646569; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as His142Arg. ClinVar contains an entry for this variant (Variation ID: 6847). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKAG2 protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000007250	SCV000027446	pathogenic	Hypertrophic cardiomyopathy 6	2001-05-15	no assertion criteria provided	literature only