Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001925451 | SCV002168622 | pathogenic | not provided | 2025-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 438 of the GALNT3 protein (p.Arg438Cys). This variant is present in population databases (rs764730691, gnomAD 0.006%). This missense change has been observed in individual(s) with tumoral calcinosis (PMID: 18982401, 21347749, 27164190; internal data). ClinVar contains an entry for this variant (Variation ID: 1403790). 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) indicates that this missense variant is expected to disrupt GALNT3 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg438 amino acid residue in GALNT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002272527 | SCV002557217 | pathogenic | Tumoral calcinosis, hyperphosphatemic, familial, 1 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hyperphosphatemic familial tumoral calcinosis 1 (MIM#211900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Tumoral calcinosis (TC) and hyperostosis-hyperphosphatemia syndrome (HHS) are a continuous spectrum. TC is characterized by the presence of ectopic calcifications around major joints, whereas HHS is characterized by recurrent long bone lesions with hyperostosis (PMID: 20358599). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 4 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated pp-GalNAc-T domain (NCBI). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg438His) has been detected in a homozygote individual with hyperostosis (PMID: 27867679). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in a compound heterozygote individual with features of both tumoral calcinosis and hyperostosis-hyperphosphatemia (PMID: 18982401). In addition, it has been reported in a homozygote individual with tumoral calcinosis (PMID: 21347749). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.(Tyr298Thrfs*5)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |