ClinVar Miner

Submissions for variant NM_014694.4(ADAMTSL2):c.1061del (p.Gly354fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV003164473 SCV002583307 likely pathogenic Lethal short-limb skeletal dysplasia, Al Gazali type 2022-10-11 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003225992 SCV003922272 likely pathogenic Geleophysic dysplasia 1 2023-05-02 criteria provided, single submitter curation The heterozygous p.Gly354AlafsTer7 variant in ADAMTSL2 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 694), in one individual with geleophysic dysplasia (PMID: 36896612). Trio exome analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 694). The p.Gly354AlafsTer7 variant in ADAMTSL2 has not been previously reported in individuals with geleophysic dysplasia 1. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 354 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of ADAMTSL2 is strongly associated to autosomal recessive geleophysic dysplasia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive geleophysic dysplasia. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015).

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