Submissions for variant NM_017837.4(PIGV):c.1369C>T (p.Leu457Phe)

gnomAD frequency: 0.00068  dbSNP: rs143676075

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490215	SCV000577025	uncertain significance	not specified	2017-10-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PIGV gene. The L457F variant in the PIGV gene has been reported previously in a heterozygous state in an individual with seizures, developmental delay, hypotonia, dysmorphic facial features, and hyperphosphatasia (Thompson et al., 2012); however, compound heterozygous variants in the PGAP3 gene have also been reported in this individual (Howard et al., 2014). The L457F variant is observed in 87/66738 (0.13%) alleles from individuals of non-Finnish European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L457F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species; however, Phenylalanine is observed at this position in evolution. Functional studies show that the L457F variant in the PIGV gene does not impair the function of the PIGV protein (Howard et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Athena Diagnostics	RCV000490215	SCV000614452	likely benign	not specified	2017-11-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765108	SCV000896330	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000983824	SCV001131853	benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000765108	SCV001258273	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000765108	SCV001522590	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 1	2019-04-19	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002526023	SCV003573642	likely benign	Inborn genetic diseases	2021-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.