ClinVar Genomic variation as it relates to human health

This missense change is denoted p.Arg119Gln (R119Q) at the protein level, and c.356 G>A at the cDNA level. The Arg119Gln variant in the PRKAG2 gene also has not been published as a disease-causing mutation or benign polymorphism. Arg119Gln results in a semi-conservative amino acid substitution of a positively-charged Arginine with a neutral Glutamine residue. No mutations in surrounding residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. The NHLBI ESP Exome Variant Server reports Arg119Gln was present in 1 out of 7019 alleles from individuals of European ancestry; however, this variant was not observed in up to 200 alleles from control individuals of Caucasian ancestry tested at GeneDx. Collectively, these findings indicate that Arg119Gln is not a common variant in this population. In summary, we cannot unequivocally determine whether Arg119Gln in the PRKAG2 gene is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).

Variant classified as Uncertain Significance - Favor Benign.

This missense variant replaces arginine with glutamine at codon 119 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). 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: 35026164). This variant has been identified in 22/251234 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.

This missense variant replaces arginine with glutamine at codon 119 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 22/251234 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.

The c.356G>A (p.R119Q) alteration is located in exon 3 (coding exon 3) of the PRKAG2 gene. This alteration results from a G to A substitution at nucleotide position 356, causing the arginine (R) at amino acid position 119 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg119Gln (R119Q; c.356G>A, exon 3) in the PRKAG2 As of December 28, 2011, no variation at codon 119 of PRKAG2 has been reported in the literature (according to searches of PubMed and Google). However, it is present as a rare variant in the NHLBI Exome Sequencing Project data set. This is a non-conservative [NOTE: semi-conservative??] amino acid substitution in which a basic, positively-charged Arginine is replaced by a neutral, polar Glutamine with a shorter sidechain. The change is at an Arginine residue that is highly conserved across 35 vertebrates, although it is a Histidine in Zebrafish. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. Of note, the variant was reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/) in 1 of 3509 Caucasian individuals and 0 of 1869 African-American individuals. The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude individuals with evidence of Mendelian cardiac disease. The variant is reported in dbSNP (www.ncbi.nlm.nih.gov/SNP) as rs142808871, but this appears to refer to the NHLBI data. GeneDx reports that the variant was absent in up to 100 presumably healthy individuals of Caucasian ancestry. It is not reported in 1000 Genomes (http://browser.1000genomes.org/index.html), which contains 1092 individuals as of December 28, 2011—over 400 of them of European ancestry. In total, therefore, the variant has been seen in 1 out of over 6500 multiethnic, non-clinically-ascertained individuals (nearly 4000 of them Caucasian like the patient).