ClinVar Miner

Submissions for variant NM_004153.4(ORC1):c.1645C>T (p.Arg549Cys)

gnomAD frequency: 0.00006  dbSNP: rs148581880
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001100036 SCV001256536 uncertain significance Meier-Gorlin syndrome 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001856357 SCV002147174 uncertain significance not provided 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 549 of the ORC1 protein (p.Arg549Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs148581880, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with ORC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 875829). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV002556023 SCV003640667 uncertain significance Inborn genetic diseases 2021-06-18 criteria provided, single submitter clinical testing The c.1645C>T (p.R549C) alteration is located in exon 11 (coding exon 10) of the ORC1 gene. This alteration results from a C to T substitution at nucleotide position 1645, causing the arginine (R) at amino acid position 549 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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