rs145303331

Positions:

chr17-16316686-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_004278.4(PIGL):c.500T>C(p.Leu167Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000739 in 1,605,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

PIGL
NM_004278.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21U:2O:1

Conservation

PhyloP100: 4.74

Variant links:

Genes affected

PIGL (HGNC:8966): (phosphatidylinositol glycan anchor biosynthesis class L) This gene encodes an enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI). Study of a similar rat enzyme suggests that this protein localizes to the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

PIGL links:

PIGL (HGNC:):

PIGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 229) in uniprot entity PIGL_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004278.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-16316686-T-C is Pathogenic according to our data. Variant chr17-16316686-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-16316686-T-C is described in Lovd as [Pathogenic]. Variant chr17-16316686-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGL	NM_004278.4 linkuse as main transcript	c.500T>C	p.Leu167Pro	missense_variant	5/7	ENST00000225609.10	NP_004269.1	Q9Y2B2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGL	ENST00000225609.10 linkuse as main transcript	c.500T>C	p.Leu167Pro	missense_variant	5/7	1	NM_004278.4	ENSP00000225609.5		Q9Y2B2-1

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000414

AC:

104

AN:

251422

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.000651

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000754

AC:

1095

AN:

1452948

Hom.:

Cov.:

AF XY:

0.000728

AC XY:

525

AN XY:

721112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.000844

Gnomad4 NFE exome

AF:

0.000910

Gnomad4 OTH exome

AF:

0.000367

GnomAD4 genome

AF:

0.000597

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000329

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CHIME syndrome

Pathogenic:10Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 06, 2012	- -
Uncertain significance, flagged submission	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Jan 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 03, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 12, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics, CHU Rennes	Jun 17, 2019	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2020

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. -

Coloboma, Congenital Heart Disease, Ichthyosiform Dermatosis, Intellectual Disability, and Ear Anomalies (CHIME) Syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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. -

Hypertelorism;C0151526:Premature birth;C0239234:Low-set ears;C0409348:Camptodactyly of finger;C0431659:Hypoplasia of scrotum;C0431904:Postaxial hand polydactyly;C1398522:Bilateral cleft lip and palate;C1827524:Wide intermamillary distance

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 09, 2014

- -

PIGL-related disorder

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.66

T;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.0

.;M

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.6

.;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.96

MVP

0.94

MPC

0.70

ClinPred

0.19

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over