ClinVar Miner

Submissions for variant NM_001146289.1(P3H1):c.2073G>A (p.Ala691=) (rs137853890)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000001321 SCV000646171 likely pathogenic Osteogenesis imperfecta type 8 2017-08-07 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the P3H1 gene. It does not directly change the encoded amino acid sequence of the P3H1 protein. This variant is present in population databases (rs137853890, ExAC 0.002%). This variant has been reported in individuals affected with autosomal recessive osteogenesis imperfecta (PMID: 19088120). ClinVar contains an entry for this variant (Variation ID: 1259). This gene is also known as LEPRE1 in the literature. An experimental study has shown that this variant strengthens a cryptic splice site in intron 14, which results in a decrease of the clinically-relevant transcript and loss of P3H1 protein expression in cells derived from individuals carrying this variant (PMID: 19088120). Truncating variants in the final exon (p.Glu719Argfs*11, p.Q722*) have been reported in individuals affected with autosomal recessive osteogenesis imperfecta, and result in loss of P3H1 protein expression (PMID: 22615817, 27864101). These variants eliminate a KDEL domain at the end of the protein (amino acids 733-736), which is important for the cellular retention and activity of certain types of proteins (PMID: 3545499). This suggests that deletion of this region, which is only present in the clinically-relevant P3H1 transcript, is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000001321 SCV000021471 pathogenic Osteogenesis imperfecta type 8 2009-04-01 no assertion criteria provided literature only

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