The c.548_549+6delAGGTTTGT variant in PIGN has been reported in one patient with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heteroz ygous state (Fleming 2016) and has been identified in 13/120594 chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enou gh to be consistent with a recessive carrier frequency. This deletion encompasse s the invariant region (+/- 1,2) of the splice consensus sequence and is predict ed to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the PIGN gene has been associated with multiple congenital anomalies-hypotonia-seizures syndrome. In summary, although additional studies a re required to fully establish its clinical significance, the c.548_549+6del var iant in PIGN is likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_176787.5(PIGN):c.548_549+6del
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.
(8)
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_176787.5(PIGN):c.548_549+6del
Variation ID: 264637 Accession: VCV000264637.24
- Type and length
-
Deletion, 8 bp
- Location
-
Cytogenetic: 18q21.33 18: 62154539-62154546 (GRCh38) [ NCBI UCSC ] 18: 59821772-59821779 (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 Oct 2, 2016 May 1, 2024 Jan 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_176787.5:c.548_549+6del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_012327.6:c.548_549+6del splice donor NC_000018.10:g.62154539_62154546del NC_000018.9:g.59821772_59821779del NG_033144.1:g.37511_37518del - Protein change
- -
- Other names
-
548_549+6DEL
- Canonical SPDI
- NC_000018.10:62154538:ACAAACCT:
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD), exomes 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00018
- 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. |
|||
| PIGN | - | - |
GRCh38 GRCh37 |
1214 | 1333 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000242057.16 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
May 10, 2016 | RCV000609184.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 26, 2022 | RCV000727335.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 3, 2018 | RCV002347968.2 |
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
(Apr 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000707637.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely pathogenic
(May 10, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple congenital anomalies-hypotonia-seizures syndrome 1
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712094.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The c.548_549+6delAGGTTTGT variant in PIGN has been reported in one patient with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heteroz ygous state (Fleming 2016) and … (more)
The c.548_549+6delAGGTTTGT variant in PIGN has been reported in one patient with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heteroz ygous state (Fleming 2016) and has been identified in 13/120594 chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enou gh to be consistent with a recessive carrier frequency. This deletion encompasse s the invariant region (+/- 1,2) of the splice consensus sequence and is predict ed to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the PIGN gene has been associated with multiple congenital anomalies-hypotonia-seizures syndrome. In summary, although additional studies a re required to fully establish its clinical significance, the c.548_549+6del var iant in PIGN is likely pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001824072.4
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27038415, 24253414, 26394714, 30609409, 30293990) (less)
|
|
|
Pathogenic
(Jun 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple congenital anomalies-hypotonia-seizures syndrome 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018802.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple congenital anomalies-hypotonia-seizures syndrome 1
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004239014.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
This PIGN variant (rs779636222) is rare (<0.1%) in a large population dataset (gnomAD: 36/276898 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. … (more)
This PIGN variant (rs779636222) is rare (<0.1%) in a large population dataset (gnomAD: 36/276898 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. It has been reported in one individual with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heterozygous state with another pathogenic variant. This 8-bp deletion (ACAAACCT) covers two coding nucleotides and six intronic nucleotides, including the canonical splice donor site and is predicted to cause aberrant pre-mRNA splicing. We consider c.548_549+6del to be pathogenic for autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome-1. (less)
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple congenital anomalies-hypotonia-seizures syndrome 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000651240.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant results in the deletion of part of exon 7 (c.548_549+6del) of the PIGN gene. It is expected to disrupt RNA splicing. Variants that … (more)
This variant results in the deletion of part of exon 7 (c.548_549+6del) of the PIGN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGN are known to be pathogenic (PMID: 24253414, 27038415). This variant is present in population databases (rs779636222, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 26394714, 30293990, 30609409). 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: 264637). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002651227.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.548_549+6delAGGTTTGT pathogenic mutation, located at the 3' end of coding exon 4 in the PIGN gene, results from a deletion of 2 coding nucleotides … (more)
The c.548_549+6delAGGTTTGT pathogenic mutation, located at the 3' end of coding exon 4 in the PIGN gene, results from a deletion of 2 coding nucleotides and 6 intronic nucleotides at positions c.548 to c.549+6, including the canonical donor site. In one study, this mutation was detected in an individual with multiple congenital anomalies-hypotonia-seizures syndrome who also carried a second PIGN alteration in trans (a gross deletion encompassing multiple exons) (Fleming, L. 2016. Am. J. Med. Genet. A 2016 Jan;170A(1):77-86). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Sep 28, 2016)
|
no assertion criteria provided
Method: literature only
|
MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000320694.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Comment on evidence:
In an infant (patient 4) with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Fleming et al. (2016) identified compound heterozygous mutations in the PIGN gene: a … (more)
In an infant (patient 4) with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Fleming et al. (2016) identified compound heterozygous mutations in the PIGN gene: a maternally inherited c.548_549+6del (c.548_549+6del, NM_176787), resulting in a frameshift (Leu183fs), and a paternally inherited intragenic deletion of part of exon 5 as well as exons 6 and 7 (606097.0008). The maternal mutation, which was found by whole-exome sequencing, was not found in the Exome Sequencing Project or ExAC databases. (less)
|
Comment:
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27038415, 24253414, 26394714, 30609409, 30293990)
Comment:
This PIGN variant (rs779636222) is rare (<0.1%) in a large population dataset (gnomAD: 36/276898 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. It has been reported in one individual with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heterozygous state with another pathogenic variant. This 8-bp deletion (ACAAACCT) covers two coding nucleotides and six intronic nucleotides, including the canonical splice donor site and is predicted to cause aberrant pre-mRNA splicing. We consider c.548_549+6del to be pathogenic for autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome-1.
Comment:
This variant results in the deletion of part of exon 7 (c.548_549+6del) of the PIGN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGN are known to be pathogenic (PMID: 24253414, 27038415). This variant is present in population databases (rs779636222, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 26394714, 30293990, 30609409). 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: 264637). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.548_549+6delAGGTTTGT pathogenic mutation, located at the 3' end of coding exon 4 in the PIGN gene, results from a deletion of 2 coding nucleotides and 6 intronic nucleotides at positions c.548 to c.549+6, including the canonical donor site. In one study, this mutation was detected in an individual with multiple congenital anomalies-hypotonia-seizures syndrome who also carried a second PIGN alteration in trans (a gross deletion encompassing multiple exons) (Fleming, L. 2016. Am. J. Med. Genet. A 2016 Jan;170A(1):77-86). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
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.548_549+6delAGGTTTGT variant in PIGN has been reported in one patient with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heteroz ygous state (Fleming 2016) and has been identified in 13/120594 chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enou gh to be consistent with a recessive carrier frequency. This deletion encompasse s the invariant region (+/- 1,2) of the splice consensus sequence and is predict ed to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the PIGN gene has been associated with multiple congenital anomalies-hypotonia-seizures syndrome. In summary, although additional studies a re required to fully establish its clinical significance, the c.548_549+6del var iant in PIGN is likely pathogenic.
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27038415, 24253414, 26394714, 30609409, 30293990)
Comment:
This PIGN variant (rs779636222) is rare (<0.1%) in a large population dataset (gnomAD: 36/276898 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. It has been reported in one individual with multiple congenital anomalies-hypotonia-seizures syndrome in a compound heterozygous state with another pathogenic variant. This 8-bp deletion (ACAAACCT) covers two coding nucleotides and six intronic nucleotides, including the canonical splice donor site and is predicted to cause aberrant pre-mRNA splicing. We consider c.548_549+6del to be pathogenic for autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome-1.
Comment:
This variant results in the deletion of part of exon 7 (c.548_549+6del) of the PIGN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGN are known to be pathogenic (PMID: 24253414, 27038415). This variant is present in population databases (rs779636222, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of multiple congenital anomalies-hypotonia-seizures syndrome (PMID: 26394714, 30293990, 30609409). 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: 264637). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.548_549+6delAGGTTTGT pathogenic mutation, located at the 3' end of coding exon 4 in the PIGN gene, results from a deletion of 2 coding nucleotides and 6 intronic nucleotides at positions c.548 to c.549+6, including the canonical donor site. In one study, this mutation was detected in an individual with multiple congenital anomalies-hypotonia-seizures syndrome who also carried a second PIGN alteration in trans (a gross deletion encompassing multiple exons) (Fleming, L. 2016. Am. J. Med. Genet. A 2016 Jan;170A(1):77-86). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
| Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. | Quinlan-Jones E | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30293990 |
| Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families. | McInerney-Leo AM | Human mutation | 2016 | PMID: 27038415 |
| Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. | Fleming L | American journal of medical genetics. Part A | 2016 | PMID: 26394714 |
| A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family. | Khayat M | American journal of medical genetics. Part A | 2016 | PMID: 26364997 |
| PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. | Ohba C | Neurogenetics | 2014 | PMID: 24253414 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PIGN | - | - | - | - |
Text-mined citations for rs779636222 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
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.