ClinVar Miner

Submissions for variant NM_212472.2(PRKAR1A):c.103A>G (p.Ile35Val) (rs377513504)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000541002 SCV000405874 likely benign Carney complex, type 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000323950 SCV000405875 likely benign Acrodysostosis 1 with or without hormone resistance 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV000541002 SCV000646280 uncertain significance Carney complex, type 1 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 35 of the PRKAR1A protein (p.Ile35Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs377513504, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a PRKAR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 324781). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on PRKAR1A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001017120 SCV001178151 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-27 criteria provided, single submitter clinical testing The p.I35V variant (also known as c.103A>G), located in coding exon 1 of the PRKAR1A gene, results from an A to G substitution at nucleotide position 103. The isoleucine at codon 35 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280560 SCV001467758 likely benign not specified 2020-12-03 criteria provided, single submitter clinical testing Variant summary: PRKAR1A c.103A>G (p.Ile35Val) results in a conservative amino acid change located in the cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251440 control chromosomes, predominantly at a frequency of 0.00062 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 331 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAR1A causing Carney Complex phenotype (1.9e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.103A>G in individuals affected with Carney Complex and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (CDKN2A c.240_253del14, p.Pro81CysfsX34), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=2, likely benign n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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