Submissions for variant NM_004278.4(PIGL):c.500T>C (p.Leu167Pro)

gnomAD frequency: 0.00062  dbSNP: rs145303331

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000023501	SCV000194637	pathogenic	CHIME syndrome	2014-04-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000301294	SCV000231063	pathogenic	not provided	2014-09-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000301294	SCV000330036	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29473937, 31980526, 22444671, 24784135, 23561846, 28371479, 25250048, 8893234, 7666399, 3041916, 31535386, 31127708)
Illumina Laboratory Services, Illumina	RCV000279778	SCV000400868	pathogenic	Coloboma, Congenital Heart Disease, Ichthyosiform Dermatosis, Intellectual Disability, and Ear Anomalies (CHIME) Syndrome	2016-06-14	criteria provided, single submitter	clinical testing	The c.500T>C (p.Leu167Pro) variant has been reported in a compound heterozygous state with either a frameshift variant, a nonsense variant or a large deletion in six patients with coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability, and ear anomalies syndrome from five unrelated families (Ng et al. 2012). All evaluated parents and siblings of the parents were found to be heterozygous carriers of the variant. Control data are unavailable for the p.Leu167Pro variant, which is reported at a frequency of 0.00091 in the European (Finnish) population of the Exome Aggregation Consortium. The variant is present in a highly conserved residue in the catalytic domain of the protein. Cell lines derived from a patient who was compound heterozygous for the p.Leu167Pro variant and a chromosome 17 deletion were deficient in two glycosylphosphatidylinositol markers, demonstrating a detrimental functional effect of the variant. Based on the evidence from the literature, the p.Leu167Pro variant is classified as pathogenic for coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability, and ear anomalies syndrome.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000301294	SCV000511579	pathogenic	not provided	2016-10-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000023501	SCV000611294	pathogenic	CHIME syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000023501	SCV000915744	pathogenic	CHIME syndrome	2017-10-03	criteria provided, single submitter	clinical testing	The PIGL c.500T>C (p.Leu167Pro) variant has been reported in a compound heterozygous state with either a frameshift variant, a nonsense variant or a large deletion in six patients with clinical features of coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability, and ear anomalies (CHIME) syndrome from five unrelated families (Ng et al. 2012). All evaluated parents and siblings of the patients were found to be heterozygous carriers of the variant. Control data are unavailable for the p.Leu167Pro variant, which is reported at a frequency of 0.00091 in the European (Finnish) population of the Exome Aggregation Consortium. The variant is present in a highly conserved residue in the catalytic domain of the protein. Cell lines derived from a patient who was compound heterozygous for the p.Leu167Pro variant and a chromosome 17 deletion were deficient in two glycosylphosphatidylinositol markers, demonstrating a detrimental functional effect of the variant. Based on the evidence from the literature, the p.Leu167Pro variant is classified as pathogenic for coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability, and ear anomalies syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000301294	SCV001421755	pathogenic	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 167 of the PIGL protein (p.Leu167Pro). This variant is present in population databases (rs145303331, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with CHIME syndrome (PMID: 22444671, 28371479). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30544). 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 PIGL protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000023501	SCV001525736	pathogenic	CHIME syndrome	2023-07-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000023501	SCV002018800	pathogenic	CHIME syndrome	2021-06-22	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000023501	SCV002072630	pathogenic	CHIME syndrome	2022-01-27	criteria provided, single submitter	clinical testing
3billion	RCV000023501	SCV002318610	pathogenic	CHIME syndrome	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030544, PMID:22444671). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 22444671, PM3_S) In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.791>=0.6, 3CNET: 0.856>=0.75).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005153). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000023501	SCV002598776	pathogenic	CHIME syndrome	2022-09-29	criteria provided, single submitter	clinical testing	Variant summary: PIGL c.500T>C (p.Leu167Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251422 control chromosomes (gnomAD). c.500T>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with CHIME Syndrome (Ng_2012, Murakami_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=11). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002513191	SCV003676550	pathogenic	Inborn genetic diseases	2020-12-11	criteria provided, single submitter	clinical testing	The c.500T>C (p.L167P) alteration is located in exon 5 (coding exon 5) of the PIGL gene. This alteration results from a T to C substitution at nucleotide position 500, causing the leucine (L) at amino acid position 167 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD), the PIGL c.500T>C alteration was observed in 0.05% (130/282820) of total alleles studied, with a frequency of 0.07% (94/129144) in the European (non-Finnish) subpopulation. This mutation has been reported in the compound heterozygous state in several individuals with CHIME syndrome as well as one homozygous individual (Ng, 2012; Knight Johnson, 2017; Ceroni, 2018). It was also identified in the homozygous state in siblings with non-syndromic ichthyosis (Onoufriadis, 2020). This amino acid position is highly conserved in available vertebrate species. The p.L167P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000023501	SCV005400572	pathogenic	CHIME syndrome	2024-10-08	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 CHIME syndrome (MIM#280000). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 130 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated PIG-L domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in multiple unrelated individuals with CHIME syndrome (PMID: 22444671). Additionally, it has been reported as pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 1010 - Functional evidence for this variant is inconclusive. A fibroblast cell line from an individual with compound heterozygous variants NM_004278.3:c.427-1G>A and NM_004278.3:c.500T>C showed deficiency in cell surface GPI anchor markers, CD59 and aerolysin (PMID: 22444671). (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_004278.3:c.427-1G>A) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000023501	SCV000044792	pathogenic	CHIME syndrome	2012-04-06	no assertion criteria provided	literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415465	SCV000492995	uncertain significance	Hypertelorism; Bilateral cleft lip and palate; Low-set ears; Premature birth; Wide intermamillary distance; Hypoplasia of scrotum; Postaxial hand polydactyly; Camptodactyly of finger	2014-04-09	flagged submission	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000023501	SCV001366933	uncertain significance	CHIME syndrome	2016-01-01	flagged submission	clinical testing	This variant was classified as: Uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000301294	SCV001742827	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000301294	SCV001927857	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000301294	SCV001951683	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Molecular Genetics, CHU Rennes	RCV000301294	SCV001963617	pathogenic	not provided	2019-06-17	no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000301294	SCV001966463	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV002508918	SCV002818440	not provided	PIGL-related disorder		no assertion provided	phenotyping only	Variant classified as Likely pathogenic and reported on 06-14-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.