Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001387322 | SCV001587925 | pathogenic | not provided | 2024-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 326 of the ALPL protein (p.Gly326Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive hypophosphatasia (PMID: 11999978). In at least one individual the data is consistent with 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 also known as p.Gly309Arg. ClinVar contains an entry for this variant (Variation ID: 1074126). 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 ALPL protein function with a positive predictive value of 95%. This variant disrupts the p.Gly326 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 29620724), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002551555 | SCV003559760 | likely pathogenic | Inborn genetic diseases | 2021-07-23 | criteria provided, single submitter | clinical testing | The c.976G>C (p.G326R) alteration is located in exon 9 (coding exon 8) of the ALPL gene. This alteration results from a G to C substitution at nucleotide position 976, causing the glycine (G) at amino acid position 326 to be replaced by an arginine (R). Based on the available evidence, this ALPL c.976G>A (p.V377I) alteration is classified as likely pathogenic for autosomal recessive hypophosphatasia (AR); however, its clinical significance for autosomal dominant hypophosphatasia (AD) is unclear. Based on data from the Genome Aggregation Database (gnomAD), the ALPL c.976G>C alteration was not observed, with coverage at this position. This alteration has been detected in the compound heterozygous state with another pathogenic alteration in a patient with lethal perinatal hypophosphatasia that also presented with seizures. Parental testing showed that this alteration was inherited from the patient's father with low serum alkaline phosphatase levels (Litmanovitz, 2002). Based on internal structural analysis, G326R decreases the structure stability. The p.G326R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
Ce |
RCV001387322 | SCV004032564 | likely pathogenic | not provided | 2023-07-01 | criteria provided, single submitter | clinical testing | ALPL: PM1, PM2, PM3, PM5:Supporting |
Baylor Genetics | RCV003469729 | SCV004191903 | likely pathogenic | Adult hypophosphatasia | 2023-10-17 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004740679 | SCV005359974 | likely pathogenic | ALPL-related disorder | 2024-01-11 | no assertion criteria provided | clinical testing | The ALPL c.976G>C variant is predicted to result in the amino acid substitution p.Gly326Arg. This variant in the compound heterozygous condition along with another ALPL missense variant has been reported in a patient with neonatal hypophosphatasia, Her father with low serum alkaline phosphatase activity is heterozygous for this variant (reported as p. Gly309Arg. Litmanovitz et al. 2002. PubMed ID: 11999978). This variant was also reported in an individual with hypophosphatasia (Pierpont et al. 2021. PubMed ID: 33579333). In addition, a different variant affecting the same amino acid (p.Gly326Val) was reported in a family with hypophosphatasia and craniosynostosis (Alghamdi et al. 2021. PubMed ID: 33937142). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. |