Submissions for variant NM_000478.6(ALPL):c.980T>G (p.Phe327Cys)

dbSNP: rs779832611

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001972665	SCV002247263	pathogenic	not provided	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 327 of the ALPL protein (p.Phe327Cys). This variant is present in population databases (rs779832611, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (Invitae). This variant is also known as F310C. ClinVar contains an entry for this variant (Variation ID: 1457572). 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.Phe327 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8954059, 9814472, 12412800, 15660230). 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276955	SCV002564894	likely pathogenic	Osteogenesis imperfecta	2022-06-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475237	SCV004195008	likely pathogenic	Adult hypophosphatasia	2024-03-26	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003475237	SCV005400351	pathogenic	Adult hypophosphatasia	2024-09-20	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: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Late-onset/mild disease is associated with monoallelic dominant negative variants or biallelic loss of function variants that retain residual enzyme activity, while early-onset/severe disease is caused by more complete loss of function variants (PMID: 20301329, 19500388). (I) 0108 - This gene is associated with both recessive and dominant disease. Severe forms of hypophosphatasia (perinatal and infantile) are generally associated with autosomal recessive disease, while the milder forms of hypophosphatasia (childhood, adult and odontohypophosphatasia) have been associated with both autosomal dominant and recessive disease (PMID: 19500388, 23688511). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301329). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301329). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (21 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 alkaline phosphatase domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Phe327Leu) has been classified as pathogenic and likely pathogenic in multiple ClinVar entries. This variant has also been identified in at least three individuals with persistent hypophosphatasaemia or hypophosphatasia (PMID: 11395499, 12412800, 28401263). p.(Phe327Ser) has been identified in an individual with low ALP levels (PMID: 21956185). p.(Phe327Gly) has also been identified in two compound heterozygote individuals with adult hypophosphatasia (PMID: 32160374). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple individuals with persistent hypophosphatasaemia, hypophosphatasia or low alkaline phosphatase. These individuals have been heterozygous or compound heterozygous for this variant (ClinVar, personal communication; PMID: 11395499, 28401263). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign