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.
ClinVar Genomic variation as it relates to human health
NM_004278.4(PIGL):c.500T>C (p.Leu167Pro)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(23)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
23
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004278.4(PIGL):c.500T>C (p.Leu167Pro)
Variation ID: 30544 Accession: VCV000030544.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p11.2 17: 16316686 (GRCh38) [ NCBI UCSC ] 17: 16220000 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 23, 2014 May 1, 2024 Jul 4, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004278.4:c.500T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004269.1:p.Leu167Pro missense NC_000017.11:g.16316686T>C NC_000017.10:g.16220000T>C NG_032651.1:g.104492T>C Q9Y2B2:p.Leu167Pro - Protein change
- L167P
- Other names
- -
- Canonical SPDI
- NC_000017.11:16316685:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00060 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00033
The Genome Aggregation Database (gnomAD), exomes 0.00041
1000 Genomes Project 30x 0.00047
Trans-Omics for Precision Medicine (TOPMed) 0.00049
1000 Genomes Project 0.00060
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
The Genome Aggregation Database (gnomAD) 0.00062
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PIGL | - | - |
GRCh38 GRCh37 |
126 | 173 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Jul 4, 2023 | RCV000023501.34 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Jun 17, 2023 | RCV000301294.21 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Jan 10, 2024 | RCV000415465.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000279778.6 | |
|
PIGL-related disorder
|
not provided (1) |
no classification provided
|
- | RCV002508918.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 11, 2020 | RCV002513191.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Coloboma, Congenital Heart Disease, Ichthyosiform Dermatosis, Intellectual Disability, and Ear Anomalies (CHIME) Syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000400868.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611294.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
|
|
|
Pathogenic
(Jan 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: yes
Allele origin:
paternal
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002072630.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318610.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Median cleft palate (present) , Patent ductus arteriosus (present) , Pulmonary artery atresia (present) , Sensorineural hearing loss disorder (present) , Sparse hair (present) , … (more)
Median cleft palate (present) , Patent ductus arteriosus (present) , Pulmonary artery atresia (present) , Sensorineural hearing loss disorder (present) , Sparse hair (present) , Ventricular septal defect (present) , Vesicoureteral reflux (present) , Wide mouth (present) , Fetal pyelectasis (present) (less)
|
|
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Pathogenic
(Apr 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000330036.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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) (less)
|
|
|
Pathogenic
(Jul 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001525736.2
First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023 |
|
|
|
Pathogenic
(Jun 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001421755.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 PIGL protein function. ClinVar contains an entry for this variant (Variation ID: 30544). 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. This variant is present in population databases (rs145303331, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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). (less)
|
|
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Pathogenic
(Dec 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003676550.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Apr 02, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000194637.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(Oct 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511579.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Sep 29, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000231063.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
|
|
|
Pathogenic
(Oct 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915744.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598776.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jun 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
CHIME syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018800.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951683.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Apr 06, 2012)
|
no assertion criteria provided
Method: literature only
|
COLOBOMA, CONGENITAL HEART DISEASE, ICHTHYOSIFORM DERMATOSIS, IMPAIRED INTELLECTUAL DEVELOPMENT, AND EAR ANOMALIES SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044792.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2022 |
Comment on evidence:
In 6 unrelated individuals with CHIME syndrome (CHIME; 280000), also known as Zunich neuroectodermal syndrome, Ng et al. (2012) identified compound heterozygosity for 2 mutations … (more)
In 6 unrelated individuals with CHIME syndrome (CHIME; 280000), also known as Zunich neuroectodermal syndrome, Ng et al. (2012) identified compound heterozygosity for 2 mutations in the PIGL gene. All patients carried a 500T-C transition in exon 5, resulting in a leu167-to-pro (L167P) substitution in a highly conserved residue in the catalytic domain on 1 allele, and a second pathogenic mutation in the PIGL gene on the other allele. Two sibs previously reported by Zunich et al. (1988) had a 1-bp deletion in exon 2 (274delC; 605947.0002), resulting in a frameshift and premature termination, on the other allele. A patient reported by Shashi et al. (1995) carried a 653C-T transition in exon 6, resulting in a gln218-to-ter (Q218X; 605947.0003), on the other allele. Another patient had a G-to-A transition in intron 3 (427-1G-A; 605947.0004) on the other allele. Finally, a patient reported by Tinschert et al. (1996) had a 1-Mb deletion of chromosome 17p12-p11.2 including the PIGL gene on the other allele. The heterozygous L167P mutation was found in 8 of nearly 13,000 control alleles from 2 large public databases: the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project and the 1000 Genomes Project database. Since all patients were of European ancestry, Ng et al. (2012) hypothesized a founder effect for this variant, which was confirmed using microsatellite markers. All PIGL mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Cell lines derived from 2 patients showed deficiency of 2 GPI anchor markers, including CD59 (107271), confirming that the disorder is due to a defect in PIGL. (less)
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|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742827.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927857.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(Jun 17, 2019)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics, CHU Rennes
Accession: SCV001963617.1
First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966463.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
PIGL-Related Disorder
Affected status: yes
Allele origin:
maternal
|
GenomeConnect, ClinGen
Accession: SCV002818440.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Premature birth (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , … (more)
Abnormality of the amniotic fluid (present) , Premature birth (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Seizure (present) , Abnormal intestine morphology (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-06-14
Testing laboratory interpretation: Likely pathogenic
|
|
|
Uncertain significance
(Apr 09, 2014)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Bilateral cleft lip and palate
Camptodactyly of finger Hypertelorism Low-set ears Postaxial hand polydactyly Premature birth Small scrotum Wide intermamillary distance
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492995.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
|
Uncertain significance
(Jan 01, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
CHIME syndrome
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366933.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Uncertain significance.
|
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| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
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.
Comment:
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)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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 PIGL protein function. ClinVar contains an entry for this variant (Variation ID: 30544). 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. This variant is present in population databases (rs145303331, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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).
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
This variant was classified as: Uncertain significance.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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 PIGL protein function. ClinVar contains an entry for this variant (Variation ID: 30544). 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. This variant is present in population databases (rs145303331, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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).
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
This variant was classified as: Uncertain significance.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data. | Hardcastle A | American journal of medical genetics. Part A | 2022 | PMID: 35904974 |
| Nonsyndromic erythrodermic ichthyosis resulting from a homozygous mutation in PIGL. | Onoufriadis A | Clinical and experimental dermatology | 2020 | PMID: 31535386 |
| Large deletion in PIGL: a common mutational mechanism in CHIME syndrome? | Ceroni JR | Genetics and molecular biology | 2018 | PMID: 29473937 |
| Alu-mediated deletion of PIGL in a Patient with CHIME syndrome. | Knight Johnson A | American journal of medical genetics. Part A | 2017 | PMID: 28371479 |
| Screening for stress-resistance mutations in the mouse. | Chick WS | Frontiers in genetics | 2014 | PMID: 25250048 |
| Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. | Murakami Y | PLoS genetics | 2014 | PMID: 24784135 |
| Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. | Hansen L | American journal of human genetics | 2013 | PMID: 23561846 |
| Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. | Ng BG | American journal of human genetics | 2012 | PMID: 22444671 |
| Zunich neuroectodermal syndrome: migratory ichthyosiform dermatosis, colobomas, and other abnormalities. | Tinschert S | Pediatric dermatology | 1996 | PMID: 8893234 |
| Neuroectodermal (CHIME) syndrome: an additional case with long term follow up of all reported cases. | Shashi V | Journal of medical genetics | 1995 | PMID: 7666399 |
| Autosomal recessive transmission of neuroectodermal syndrome. | Zunich J | Archives of dermatology | 1988 | PMID: 3041916 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PIGL | - | - | - | - |
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Text-mined citations for rs145303331 ...
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Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.