ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.219C>G (p.Ala73=) (rs730881679)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590197 SCV000210948 uncertain significance not provided 2014-08-26 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.262C>G at the cDNA level, p.Arg88Gly (R88G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDKN2A Arg88Gly 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. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Arg88Gly occurs at a position that is poorly conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CDKN2A Arg88Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590197 SCV000695336 uncertain significance not provided 2016-02-08 criteria provided, single submitter clinical testing Variant summary: The c.219C>G variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is not found in 82880 control chromosomes. c.219C>T, a variant resulting in same p.Ala73Ala, has been reported in one sporadic melanoma sample (PMID 9036865). Functional studies showed that p.Ala73Ala was comparable to wild-type in protein interactions, cellular distribution, and cell cycle inhibitory function (PMID 11518711, 20340136). However, variant of interest may lead to a missense change p.Arg88Gly if it is translated into a different transcript (p14ARF). The effect of this missense has not been studied. In addition, one clinical laboratory reported this variant as c.262C>G/p.Arg88Gly with a classsifcation of VUS. Taken together, this variant was classified as VUS.
Invitae RCV001227642 SCV001400008 likely benign Hereditary melanoma 2019-11-06 criteria provided, single submitter clinical testing

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