ClinVar Miner

Submissions for variant NM_000075.4(CDK4):c.229G>A (p.Val77Ile) (rs730881670)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160398 SCV000210929 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted CDK4 c.229G>A at the cDNA level, p.Val77Ile (V77I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDK4 Val77Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. CDK4 Val77Ile occurs at a position that is conserved across species and is located within the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether CDK4 Val77Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000234117 SCV000283395 uncertain significance Hereditary melanoma 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 77 of the CDK4 protein (p.Val77Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDK4-related disease. ClinVar contains an entry for this variant (Variation ID: 182404). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.
Ambry Genetics RCV000571279 SCV000669098 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-13 criteria provided, single submitter clinical testing The p.V77I variant (also known as c.229G>A), located in coding exon 2 of the CDK4 gene, results from a G to A substitution at nucleotide position 229. The valine at codon 77 is replaced by isoleucine, 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.

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