ClinVar Miner

Submissions for variant NM_000095.3(COMP):c.1318G>C (p.Gly440Arg)

dbSNP: rs1601053997
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001082 SCV001158215 likely pathogenic not specified 2019-02-15 criteria provided, single submitter clinical testing The p.Gly440Arg variant was reported in a four-year-old girl with disproportionate short stature due to growth retardation, including indications of mild scoliosis and genu varum (Cao 2011). A different variant resulting in the same amino acid change has also been identified in multiple patients, including a five-year-old girl with metaphyseal flaring of the distal femur, and a pair of male siblings with pseudoachondroplasia (Kim 2011 and Loughlin 1998). The p.Gly440Arg is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD). The glycine at position 440 is highly conserved in the calcium-binding type 3 repeat domain and computational analyses of the effects of the p.Gly440Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Overall the p.Gly440Arg variant meets our criteria for a classification of likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001869425 SCV002161598 pathogenic not provided 2023-03-22 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COMP protein function. ClinVar contains an entry for this variant (Variation ID: 811306). This missense change has been observed in individuals with pseudoachondroplasia or multiple epiphyseal dysplasia (PMID: 9452026, 15756302, 21644213, 21965141). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 440 of the COMP protein (p.Gly440Arg).

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