ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.587C>T (p.Ser196Phe)

gnomAD frequency: 0.00001  dbSNP: rs267601424
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159000 SCV000208941 uncertain significance not provided 2013-02-11 criteria provided, single submitter clinical testing p.Ser196Phe (TCC>TTC): c.587 C>T in exon 4 of the PRKAG2 gene (NM_016203.3) The Ser196Phe variant in the PRKAG2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ser196Phe results in a non-conservative amino acid substitution of a polar Serine with a non-polar Phenylalanine, it occurs at a position that is not well conserved across species. Also, no mutations in nearby codons have been reported in association with WPW, indicating this region of the protein may be tolerant of change. Nevertheless, the Ser196Phe 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.With the clinical and molecular information available at this time, we cannot definitively determine if Ser196Phe is a disease-causing mutation or a rare benign variant. The pathogenic role for this variant would be supported if it co-segregates with a HCM or WPW phenotype. The variant is found in HCM panel(s).
Invitae RCV001052457 SCV001216669 uncertain significance Lethal congenital glycogen storage disease of heart 2023-09-17 criteria provided, single submitter clinical testing 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 76800). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is present in population databases (rs267601424, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 196 of the PRKAG2 protein (p.Ser196Phe).
Color Diagnostics, LLC DBA Color Health RCV001186288 SCV001352669 uncertain significance Cardiomyopathy 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 196 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 PRKAG2-related disorders in the literature. This variant has been identified in 3/251458 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001186288 SCV002043493 uncertain significance Cardiomyopathy 2019-08-21 criteria provided, single submitter clinical testing

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