ClinVar

Description

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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 3 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (PMID: 27867679, ClinVar, DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported likely pathogenic in ClinVar and detected in a compound heterozygote individual with tumoral calcinosis (PMID: 27867679). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign