Submissions for variant NM_001346754.2(PIGW):c.617_620del (p.Val206fs)

dbSNP: rs753385776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000427391	SCV000511695	likely pathogenic	not provided	2016-12-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000427391	SCV001151273	likely pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001170042	SCV001251819	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 5	2020-05-03	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270043	SCV001448771	likely pathogenic	Global developmental delay; Abnormal skeletal morphology; Cleft palate	2018-12-03	criteria provided, single submitter	clinical testing
Invitae	RCV001170042	SCV002288633	uncertain significance	Hyperphosphatasia with intellectual disability syndrome 5	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val206Glyfs*3) in the PIGW gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 299 amino acid(s) of the PIGW protein. This variant is present in population databases (rs753385776, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with PIGW-related conditions. ClinVar contains an entry for this variant (Variation ID: 377301). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002524736	SCV003694413	pathogenic	Inborn genetic diseases	2022-08-22	criteria provided, single submitter	clinical testing	The c.617_620delTTTG (p.V206Gfs*3) alteration, located in exon 2 (coding exon 1) of the PIGW gene, consists of a deletion of 4 nucleotides from position 617 to 620, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration occurs at the 3' terminus of the PIGW gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 299 amino acids of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.617_620delTTTG allele has an overall frequency of 0.02% (69/282804) total alleles studied. The highest observed frequency was 0.08% (29/35438) of Latino alleles. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000427391	SCV003933566	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation, as the last 229 amino acids are replaced with 2 different amino acids
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235205	SCV003934242	uncertain significance	not specified	2023-05-03	criteria provided, single submitter	clinical testing	Variant summary: PIGW c.617_620delTTTG (p.Val206GlyfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 0.00025 in 251406 control chromosomes.To our knowledge, no occurrence of c.617_620delTTTG in individuals affected with Hyperphosphatasia With Mental Retardation Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2), Likely Pathogenic (n=3) and Pathogenic (n=1). Based on the evidence outlined above and the fact that there is not enough evidence to establish loss-of-function as a mechanism of disease for this gene, the variant was classified as uncertain significance.