Submissions for variant NM_016203.4(PRKAG2):c.186G>T (p.Lys62Asn)

gnomAD frequency: 0.00001  dbSNP: rs369687307

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038928	SCV000062606	uncertain significance	not specified	2010-12-02	criteria provided, single submitter	clinical testing	The Lys62Asn variant has not been reported in the literature. Lysine (Lys) at p osition 62 is conserved in evolutionary distant species, suggesting that a chang e would not be tolerated. In addition, this variant has not been identified in over 1000 Caucasian probands (2000 chromosomes) tested by our laboratory. This l ow frequency increases the likelihood that the variant is pathogenic. However, the Lys62Asn variant is located outside the CBS domain region where all pathogen ic PRKAG2 variants have been identified to date (Oliveira 2003), raising the pos sibility that it is not disease causing in isolation. In summary, additional stu dies are necessary to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001371678	SCV001568252	uncertain significance	Lethal congenital glycogen storage disease of heart	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 62 of the PRKAG2 protein (p.Lys62Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 45707). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003996414	SCV004842325	uncertain significance	Hypertrophic cardiomyopathy	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 62 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>T nucleotide substitution at the last nucleotide of exon 2 of the PRKAG2 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 2/245592 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.
Ambry Genetics	RCV004018883	SCV005011585	uncertain significance	Cardiovascular phenotype	2020-09-21	criteria provided, single submitter	clinical testing	The c.186G>T (p.K62N) alteration is located in exon 2 (coding exon 2) of the PRKAG2 gene. This alteration results from a G to T substitution at nucleotide position 186, causing the lysine (K) at amino acid position 62 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.