ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1988A>G (p.Asn663Ser)

gnomAD frequency: 0.00001  dbSNP: rs1007286459
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000692624 SCV000820456 benign Retinoblastoma 2023-08-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV002422501 SCV002718532 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-04 criteria provided, single submitter clinical testing The p.N663S variant (also known as c.1988A>G), located in coding exon 20 of the RB1 gene, results from an A to G substitution at nucleotide position 1988. The asparagine at codon 663 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well 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.
All of Us Research Program, National Institutes of Health RCV000692624 SCV004844712 uncertain significance Retinoblastoma 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 663 of the RB1 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 RB1-related disorders in the literature. This variant has been identified in 1/251492 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.
PreventionGenetics, part of Exact Sciences RCV003892543 SCV004715757 uncertain significance RB1-related disorder 2023-10-30 no assertion criteria provided clinical testing The RB1 c.1988A>G variant is predicted to result in the amino acid substitution p.Asn663Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/13-49033851-A-G). It has conflicting interpretations of benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/460359/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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