Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV001089998 | SCV001245039 | likely pathogenic | Arterial calcification, generalized, of infancy, 1 | 2019-01-05 | criteria provided, single submitter | clinical testing | A heterozygous missense variant, NM_006208.2(ENPP1):c.2376T>A, has been identified in exon 23 of 25 of the ENPP1 gene. The variant is predicted to result in a moderate amino acid change from an Asparagine to a Lysine at position 792 of the protein, NM_006208.2(ENPP1):p.(Asn792Lys). The Asparagine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Nuclease-like functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), however three alternative residue changes have been reported in the gnomAD database (total of 23 het and 1 hom). This variant has not been previously reported in clinical cases. A different amino acid change in the same codon, p.(Asn792Ser) has previously been described as compound heterozygous pathogenic variant in two independent infants with infantile arterial calcification (Rutsch et al., 2003). Functional data for the N792S variant showed reduced enzyme activity (Rutsch et al., 2003). Analysis of parental samples indicated this variant was paternally inherited. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. The presence of these two variants in trans confirms a compound heterozygous mode of inheritance which is consistent with generalised infant arterial calcification. |
| Invitae | RCV001862668 | SCV002201835 | uncertain significance | not provided | 2023-09-23 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Asn792 amino acid residue in ENPP1. Other variant(s) that disrupt this residue have been observed in individuals with ENPP1-related conditions (PMID: 12881724, 33465815), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ENPP1 protein function. ClinVar contains an entry for this variant (Variation ID: 870422). This missense change has been observed in individual(s) with autosomal recessive ENPP1-related conditions (PMID: 32573669, 33465815). This variant is present in population databases (rs137853273, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 792 of the ENPP1 protein (p.Asn792Lys). |