ClinVar Miner

Submissions for variant NM_004278.4(PIGL):c.500T>C (p.Leu167Pro) (rs145303331)

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Total submissions: 13
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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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000301294 SCV000231063 pathogenic not provided 2014-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000301294 SCV000330036 likely pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the PIGL gene. The L167P variant, described as a possible founder missense variant, has been previously reported in multiple unrelated individuals with CHIME syndrome who harbored a second PIGL variant; however, parental studies confirming phase were not reported (Ng et al., 2012; Knight Johnson et al., 2017; Ceroni et al., 2018). Functional studies show that the variant leads to deficiency of GPI anchor markers, suggesting deficiency of GPI (Ng et al., 2012). The L167P variant is observed in 19/25794 (0.07%) alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). The L167P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Illumina Clinical Services Laboratory,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.
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; Scrotal hypoplasia; Postaxial hand polydactyly; Camptodactyly of finger 2014-04-09 criteria provided, single submitter clinical testing
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 Clinical Services Laboratory,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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000023501 SCV001366933 uncertain significance CHIME syndrome 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
Invitae RCV000301294 SCV001421755 pathogenic not provided 2019-08-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 167 of the PIGL protein (p.Leu167Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs145303331, ExAC 0.09%). This variant has been observed in several individuals affected with CHIME syndrome (PMID: 22444671, 28371479). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30544). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000023501 SCV001525736 pathogenic CHIME syndrome 2018-10-18 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000023501 SCV000044792 pathogenic CHIME syndrome 2012-04-06 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000301294 SCV001742827 pathogenic not provided no assertion criteria provided clinical testing

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