Submissions for variant NM_016203.4(PRKAG2):c.1004T>C (p.Met335Thr)

dbSNP: rs730880978

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159008	SCV000208949	uncertain significance	not specified	2016-08-19	criteria provided, single submitter	clinical testing	The M335T variant has previously been reported in a 42 year-man with HCM and paroxysmal drug-resistant atrial fibrillation (Van Belle et al., 2008). In addition, this variant was found to segregate with disease in this man's father, who was reported to have the same phenotype (Van Belle et al., 2008). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M335T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, although the M335T variant has been observed in other unrelated individuals referred for HCM genetic testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the M335T variant. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000535478	SCV000640336	likely pathogenic	Lethal congenital glycogen storage disease of heart	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 335 of the PRKAG2 protein (p.Met335Thr). 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: 18811822, 32646569; Invitae). ClinVar contains an entry for this variant (Variation ID: 181477). 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 tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001185250	SCV001351423	uncertain significance	Cardiomyopathy	2019-01-16	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant is located in the CBS domain 1 of the PRKAG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two related individuals affected with hypertrophic cardiomyopathy and paroxysmal atrial fibrillation (PMID: 18811822). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Ambry Genetics	RCV002399578	SCV002714316	uncertain significance	Cardiovascular phenotype	2023-06-14	criteria provided, single submitter	clinical testing	The p.M335T variant (also known as c.1004T>C), located in coding exon 8 of the PRKAG2 gene, results from a T to C substitution at nucleotide position 1004. The methionine at codon 335 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a case report of an individual with hypertrophic cardiomyopathy (HCM) (Van Belle Y et al. Pacing Clin Electrophysiol, 2008 Oct;31:1358-61). Additionally, this alteration was detected in a HCM cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786200	SCV000924911	uncertain significance	not provided	2017-09-07	no assertion criteria provided	provider interpretation	p.Met335Thr (c.1004T>C) in PRKAG2 (NM_016203.3) SCICD: variant of uncertain significance, probably disease causing. The rarity and case data support pathogenicity, however since we don't have specific or reliable phenotypic data several of the laboratory cases we can not be confident in pathogenicity. Cases: It has been seen in one published case with matching phenotype (van Belle et al) and several cases within private laboratory datasets without detail available on phenotype. Reference data: The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is >34x.