Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Rady Children's Institute for Genomic Medicine, |
RCV000853319 | SCV000996171 | pathogenic | Coronary sclerosis, medial, of infancy | 2018-07-17 | criteria provided, single submitter | clinical testing | This missense variant is also predicted to affect the canonical splice donor site of intron 9 of 25 by multiple splice prediction tools, and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with generalized arterial calcification of infancy (PMID: 15605415, 15940697). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1025G>T, p.Gly342Val variant is classified as Pathogenic. |
| Invitae | RCV001851855 | SCV002318084 | likely pathogenic | not provided | 2021-10-04 | criteria provided, single submitter | clinical testing | 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 13591). This missense change has been observed in individual(s) with autosomal recessive generalized arterial calcification of infancy (PMID: 15940697). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 342 of the ENPP1 protein (p.Gly342Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | RCV000014560 | SCV000034814 | pathogenic | Arterial calcification, generalized, of infancy, 1 | 2005-07-15 | no assertion criteria provided | literature only |