Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fulgent Genetics, |
RCV005046849 | SCV005666689 | pathogenic | Arterial calcification, generalized, of infancy, 1; Type 2 diabetes mellitus; Hypophosphatemic rickets, autosomal recessive, 2; Hypopigmentation-punctate palmoplantar keratoderma syndrome; Inherited obesity | 2024-03-04 | criteria provided, single submitter | clinical testing | |
| Genomic Medicine Center of Excellence, |
RCV000779491 | SCV004807409 | likely pathogenic | Arterial calcification, generalized, of infancy, 1 | 2024-03-26 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV001157114 | SCV002521261 | pathogenic | Hypophosphatemic rickets, autosomal recessive, 2 | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:12881724). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:12881724). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000547983). A different missense change at the same codon (p.Arg481Gln) has been reported to be associated with ENPP1 related disorder (PMID: 26857895). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV001855391 | SCV002246995 | pathogenic | not provided | 2025-11-25 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 481 of the ENPP1 protein (p.Arg481Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs373044722, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive ENPP1-related conditions (PMID: 12881724, 29244957, 31826312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 547983). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ENPP1 protein function. Studies have shown that this missense change results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 12881724). For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV000779491 | SCV001521013 | pathogenic | Arterial calcification, generalized, of infancy, 1 | 2020-01-17 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Illumina Laboratory Services, |
RCV000779491 | SCV000916124 | likely pathogenic | Arterial calcification, generalized, of infancy, 1 | 2018-10-25 | criteria provided, single submitter | clinical testing | The ENPP1 c.1441C>T (p.Arg481Trp) missense variant has been reported in at least two studies and is found in a compound heterozygous state in two unrelated individuals with generalized arterial calcification of infancy (Rutsch et al. 2003; Rutsch et al. 2008). One individual is reported to also have an affected sibling detected from prenatal diagnosis (Rutsch et al. 2008). The p.Arg481Trp variant was absent from 100 controls but is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project but this is based on one allele so the variant is presumed to be rare. Rutsch et al. (2003) performed RT-PCR studies on total RNA from one of the probands that showed that the p.Arg481Trp variant results in skipping of exon 15 which causes a frameshift. Transfection experiments in osteoblastic osteosarcoma cells showed the variant resulted in reduced activity to 30-40% of that associated with wild type ENPP1. The Arg481 residue lies in the catalytic domain of the ENPP1 protein and is conserved in human, mouse and rat ENPP1 and human ENPP3. Based on the evidence, the p.Arg481Trp variant is classified as likely pathogenic for generalized arterial calcification of infancy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Mayo Clinic Laboratories, |
RCV000660584 | SCV000782696 | pathogenic | Arterial calcification, generalized, of infancy, 1; Hypophosphatemic rickets, autosomal recessive, 2 | 2017-06-28 | criteria provided, single submitter | clinical testing |