ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.1006G>A (p.Val336Ile)

dbSNP: rs727504707
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000155991 SCV000205703 uncertain significance not specified 2013-08-09 criteria provided, single submitter clinical testing The Val336Ile variant in PRKAG2 has not been reported in individuals with cardio myopathy or in large population studies. It is located in the CBS domain region of the PRKAG2 protein, where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003). Valine (Val) at position 336 is highly conserved in ma mmals and across evolutionarily distant species. However, additional computation al analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that the Val336Ile variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. This variant is locat ed in the first base of the exon, which is part of the 3? splice region. Computa tional tools do not suggest an impact to splicing; however, this information is not predictive enough to DETERMINE/RULE OUT pathogenicity. In summary, additiona l information is needed to fully assess the clinical significance of this varian t.
GeneDx RCV000766635 SCV000208950 uncertain significance not provided 2018-10-05 criteria provided, single submitter clinical testing The V336I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been seen in one other individual referred for HCM testing at GeneDx, and is classified in ClinVar as a variant of uncertain significance by an outside laboratory (SCV000205703.3; Landrum et al., 2016). The V336I 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. This substitution occurs at a position that is conserved across species. Nonetheless, V336I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000617676 SCV000740204 uncertain significance Cardiovascular phenotype 2023-03-17 criteria provided, single submitter clinical testing The p.V336I variant (also known as c.1006G>A) is located in coding exon 9 of the PRKAG2 gene. The valine at codon 336 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 9. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000815410 SCV000955861 uncertain significance Lethal congenital glycogen storage disease of heart 2024-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 336 of the PRKAG2 protein (p.Val336Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 179205). Invitae Evidence 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 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. This variant disrupts the p.Val336 amino acid residue in PRKAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28431061; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000155991 SCV000280421 uncertain significance not specified 2014-05-30 no assertion criteria provided clinical testing 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.Val336Ile (c.1006G>A) in the PRKAG2 gene. This variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign. Mutation Taster predicts this variant to be disease-causing, noting that the alteration is within a used splice site and is likely to disturb normal splicing. Val336Ile results in a conservative amino acid substitution of one non-polar amino acid with another. The valine at codon 336 is mostly conserved across species, although in Celegans and Dmelanogaster it is reported as alanine and glutamic acid, respectively. Neighboring amino acids are conserved. GeneDx reports that no mutations in nearby residues have been reported in HGMD in association with Wolff-Parkinson-White syndrome or cardiomyopathy. In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 336 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/13/13). Note that this dataset does not completely match the patient's ancestry. There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 7/13/13). GeneDx did not give control data.

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