ClinVar Miner

Submissions for variant NM_000095.3(COMP):c.1405GAC[4] (p.Asp473del)

dbSNP: rs193922900
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486037 SCV000564908 pathogenic not provided 2020-09-11 criteria provided, single submitter clinical testing Most common pathogenic variant in the COMP gene and has been reported previously in association with pseudoachondroplasia (Hecht et al., 1995; Suleman et al., 2012; Briggs et al., 2014); Published functional studies in mice demonstrate abnormal growth plates with disorganized chondrocyte columns resulting in the development of short-limb dwarfism (Suleman et al., 2012); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32347019, 29309831, 7670471, 24595329, 17570134, 11084047, 22006726, 23956175, 30138938)
Invitae RCV000486037 SCV000935843 pathogenic not provided 2023-10-04 criteria provided, single submitter clinical testing This variant, c.1417_1419del, results in the deletion of 1 amino acid(s) of the COMP protein (p.Asp473del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with pseudoachondroplasia and spondyloepiphyseal dysplasia (PMID: 7670471, 21922596, 30138938). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40988). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects COMP function (PMID: 11084047, 17570134, 22006726, 23956175). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001332185 SCV001524422 pathogenic Multiple epiphyseal dysplasia type 1 2019-01-02 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7670471, 17570134, 23956175, 22006726, 11084047]
Blueprint Genetics RCV000486037 SCV001832278 pathogenic not provided 2019-11-20 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000033880 SCV002512641 pathogenic Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome 2021-09-25 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate
Neuberg Centre For Genomic Medicine, NCGM RCV000033880 SCV004100459 pathogenic Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome criteria provided, single submitter clinical testing The in-frame deletion p.D473del in COMP (NM_000095.3) has been observed in individual(s) with pseudoachondroplasia and spondyloepiphyseal dysplasia ( J T Hecht et al, 1995; Jackson et al, 2011; Huang et al, 2018). This variant has been reported to affect COMP protein function ( Chen et al, 2008; Hartley et al, 2013). Additionally, the variant has been reported to ClinVar as Pathogenic. The p.D473del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a aspartic acid at position 473 of the COMP gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.1417 in COMP is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000033880 SCV000029985 pathogenic Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome 2002-05-01 no assertion criteria provided literature only
GeneReviews RCV000033880 SCV000057788 not provided Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome no assertion provided literature only

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