ClinVar Genomic variation as it relates to human health
NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys)
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.
(33)
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
33
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001100913.3(PACS2):c.625G>A (p.Glu209Lys)
Variation ID: 495141 Accession: VCV000495141.89
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.33 14: 105368112 (GRCh38) [ NCBI UCSC ] 14: 105834449 (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 Mar 8, 2018 Nov 24, 2024 Oct 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001100913.3:c.625G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001094383.2:p.Glu209Lys missense NM_001243127.3:c.424G>A NP_001230056.1:p.Glu142Lys missense NM_015197.4:c.625G>A NP_056012.2:p.Glu209Lys missense NC_000014.9:g.105368112G>A NC_000014.8:g.105834449G>A - Protein change
- E209K, E142K
- Other names
-
p.Glu209Lys
- Canonical SPDI
- NC_000014.9:105368111:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
- 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. |
|||
| PACS2 | - | - |
GRCh38 GRCh37 |
975 | 1126 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 5, 2016 | RCV000585789.8 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2021 | RCV001420210.8 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2022 | RCV001813790.8 | |
| Pathogenic (18) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV000677126.36 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV000782018.47 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 16, 2018 | RCV001265915.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 13, 2022 | RCV002265812.7 | |
|
PACS2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 19, 2024 | RCV004752955.1 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Aug 05, 2016)
|
criteria provided, single submitter
Method: research
|
Intellectual disability
Affected status: yes
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000693433.1
First in ClinVar: Mar 08, 2018 Last updated: Mar 08, 2018 |
|
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893337.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139524.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
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Pathogenic
(Aug 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000920482.2
First in ClinVar: Jun 03, 2019 Last updated: Jun 07, 2020 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Sep 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001521920.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
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Pathogenic
(Apr 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV001622630.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
PP5_very strong;PM2_supporting;PP2_supporting
Clinical Features:
Seizure (present) , Global developmental delay (present) , Dandy-Walker malformation (present) , Short attention span (present) , Genu valgum (present) , Pes planus (present) , … (more)
Seizure (present) , Global developmental delay (present) , Dandy-Walker malformation (present) , Short attention span (present) , Genu valgum (present) , Pes planus (present) , Pes valgus (present) , Hypotonia (present) , Cerebellar vermis hypoplasia (present) , Patent foramen ovale (present) (less)
Sex: female
|
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 1
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061287.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.625G>A;p.(Glu209Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 495141; OMIM: 610423.0001; PMID: 29656858) … (more)
The c.625G>A;p.(Glu209Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 495141; OMIM: 610423.0001; PMID: 29656858) - PS4.This variant is not present in population databases (rs1555408401, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 29656858) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
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Pathogenic
(Jan 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051701.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS2_very_strong, PS3, PS4, PM2
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001554485.2
First in ClinVar: Apr 13, 2021 Last updated: Mar 02, 2022 |
|
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Pathogenic
(Apr 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
de novo
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501130.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
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Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
unknown
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515362.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572655.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.23; 3Cnet: 0.20). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495141). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29656858). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29656858). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hydrocephalus (present) , Global developmental delay (present) , Bilateral tonic-clonic seizure (present) , Dysphagia (present)
|
|
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Pathogenic
(Oct 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577524.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PS3, PM1, PM2, PP3, PP5
|
|
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Pathogenic
(Apr 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444087.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Nevus sebaceous (present) , Hydronephrosis (present) , Muscular hypotonia (present) , Microcephaly (present) , Seizures (present) , Allergy (present) , Congenital microcephaly (present) , Neonatal … (more)
Nevus sebaceous (present) , Hydronephrosis (present) , Muscular hypotonia (present) , Microcephaly (present) , Seizures (present) , Allergy (present) , Congenital microcephaly (present) , Neonatal hypoglycemia (present) , Oligohydramnios (present) , Telecanthus (present) , Long philtrum (present) , Smooth philtrum (present) , Clinodactyly (present) , Eczema (present) , Frontal bossing (present) , Prominent forehead (present) , Hypertelorism (present) , Global developmental delay (present) , Renal cyst (present) , Increased CSF protein (present) , Thin upper lip vermilion (present) , Low-set ears (present) , Epicanthus (present) , Wide nasal bridge (present) , Depressed nasal bridge (present) , Choroid plexus cyst (present) , Genu varum (present) , Mongolian blue spot (present) , Prominent metopic ridge (present) , Ear malformation (present) , Ureteropelvic junction obstruction (present) , Small for gestational age (present) (less)
Sex: male
Ethnicity/Population group: African American
|
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Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818256.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
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Pathogenic
(Feb 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001873688.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); Not observed at significant frequency in large population cohorts … (more)
Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28628100, 29656858, 28867141, 28135719, 30684285, 32416568, 32166392, 28191890, 30290155, 30904718, 31231135, 31036916, 25741868, 31130284, 34489640, 33243487, 33240318, 33461828, 33004838) (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003920843.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
A Heterozygous Missense variant c.625G>A in Exon 6 of the PACS2 gene that results in the amino acid substitution p.Glu209Lys was identified. The observed variant … (more)
A Heterozygous Missense variant c.625G>A in Exon 6 of the PACS2 gene that results in the amino acid substitution p.Glu209Lys was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variation ID: 495141). The variant has been previously reported for Developmental and epileptic encephalopathy by Olson HE, et al., 2018. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function (Olson HE, et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
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Pathogenic
(Nov 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175387.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
|
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Pathogenic
(Jul 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004223968.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP4, PM2, PS2_very_strong, PS4
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001575671.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the PACS2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the PACS2 protein (p.Glu209Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PACS2-related conditions (PMID: 29656858). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 495141). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004801932.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Clinical Features:
Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Decreased liver function (present) , Thrombocytopenia (present) , Leukopenia (present) , Elevated circulating hepatic … (more)
Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Decreased liver function (present) , Thrombocytopenia (present) , Leukopenia (present) , Elevated circulating hepatic transaminase concentration (present) (less)
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Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: research
|
Developmental and epileptic encephalopathy, 66
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801164.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934285.3
First in ClinVar: Sep 25, 2021 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS2_VSTR,PS4,PS3_SUP,PM2_SUP
Clinical Features:
Generalized-onset seizure (present) , Moderate global developmental delay (present)
Sex: female
|
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Pathogenic
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197062.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
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Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248885.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PACS2: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 15
|
|
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Pathogenic
(Oct 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398915.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function has been suggested (PMID: 29656858). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variability of clinical severity has been reported in a family (PMID: 35770754). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in many clinical testing laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Dec 12, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
germline
|
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000925830.1
First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 2019 |
|
|
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Likely pathogenic
(Jul 07, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
de novo
|
Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV001434001.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Age: 0-9 years
Sex: male
|
|
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Pathogenic
(Nov 24, 2020)
|
no assertion criteria provided
Method: literature only
|
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 66
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000803196.3
First in ClinVar: Aug 06, 2018 Last updated: Nov 28, 2020 |
Comment on evidence:
In 14 unrelated patients with developmental and epileptic encephalopathy-66 (DEE66; 618067), Olson et al. (2018) identified a de novo heterozygous c.625G-A transition (c.625G-A, NM_001100913.2) in … (more)
In 14 unrelated patients with developmental and epileptic encephalopathy-66 (DEE66; 618067), Olson et al. (2018) identified a de novo heterozygous c.625G-A transition (c.625G-A, NM_001100913.2) in the PACS2 gene, resulting in a glu209-to-lys (E209K) substitution at a highly conserved residue in an acid hydrophobic domain that leads to polarity and protein conformation changes. The mutation in the first 2 patients was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not found in the gnomAD or Exome Variant Server databases. By international data-sharing, 12 additional individuals with a similar phenotype and a de novo heterozygous E209K mutation were ascertained. All mutations had been found through research or clinical diagnostic whole-exome sequencing, suggesting that this recurrent mutation is responsible for the phenotype. The patients had onset of various types of seizures in the first days or weeks of life. (less)
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Pathogenic
(Jul 13, 2022)
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no assertion criteria provided
Method: clinical testing
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Seizure
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV002547310.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Sex: female
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Pathogenic
(Sep 08, 2002)
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no assertion criteria provided
Method: research
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Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
de novo
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Center of Excellence for Medical Genomics, Chulalongkorn University
Accession: SCV002570076.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
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Pathogenic
(Feb 08, 2023)
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no assertion criteria provided
Method: research
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Developmental and epileptic encephalopathy, 66
Affected status: yes
Allele origin:
de novo
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Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo
Accession: SCV003914746.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Sep 19, 2024)
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no assertion criteria provided
Method: clinical testing
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PACS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005352201.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The PACS2 c.625G>A variant is predicted to result in the amino acid substitution p.Glu209Lys. This variant has been documented in a large number of cases … (more)
The PACS2 c.625G>A variant is predicted to result in the amino acid substitution p.Glu209Lys. This variant has been documented in a large number of cases as a recurrent de novo cause of disease and the defining pathogenic variant in PACS2 (see for example, Olson et al. 2018. PubMed ID: 30290155). In vitro analysis in the Olson study indicated that this variant disrupts autoregulation and companion protein interactions. This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. (less)
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Citation text
Olson, H. E., Jean-Marcais, N., Yang, E., Heron, D., Tatton-Brown, K., van der Zwaag, P. A., Bijlsma, E. K., Krock, B. L., Backer, E., Kamsteeg, E.-J., Sinnema, M., Reijnders, M. R. F., and 46 others A recurrent de novo PACS2 heterozygous missense variant causes neonatal-onset developmental epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. Am. J. Hum. Genet. 102: 995-1007, 2018. Note: Erratum: Am. J. Hum. Genet. 103: 631 only, 2018.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
PP5_very strong;PM2_supporting;PP2_supporting
Comment:
The c.625G>A;p.(Glu209Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 495141; OMIM: 610423.0001; PMID: 29656858) - PS4.This variant is not present in population databases (rs1555408401, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 29656858) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
PS2_very_strong, PS3, PS4, PM2
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.23; 3Cnet: 0.20). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495141). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29656858). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29656858). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS3, PM1, PM2, PP3, PP5
Comment:
Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28628100, 29656858, 28867141, 28135719, 30684285, 32416568, 32166392, 28191890, 30290155, 30904718, 31231135, 31036916, 25741868, 31130284, 34489640, 33243487, 33240318, 33461828, 33004838)
Comment:
A Heterozygous Missense variant c.625G>A in Exon 6 of the PACS2 gene that results in the amino acid substitution p.Glu209Lys was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variation ID: 495141). The variant has been previously reported for Developmental and epileptic encephalopathy by Olson HE, et al., 2018. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function (Olson HE, et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Comment:
BP4, PM2, PS2_very_strong, PS4
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the PACS2 protein (p.Glu209Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PACS2-related conditions (PMID: 29656858). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 495141). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PS2_VSTR,PS4,PS3_SUP,PM2_SUP
Comment:
PACS2: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function has been suggested (PMID: 29656858). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variability of clinical severity has been reported in a family (PMID: 35770754). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in many clinical testing laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The PACS2 c.625G>A variant is predicted to result in the amino acid substitution p.Glu209Lys. This variant has been documented in a large number of cases as a recurrent de novo cause of disease and the defining pathogenic variant in PACS2 (see for example, Olson et al. 2018. PubMed ID: 30290155). In vitro analysis in the Olson study indicated that this variant disrupts autoregulation and companion protein interactions. This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic.
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:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
PP5_very strong;PM2_supporting;PP2_supporting
Comment:
The c.625G>A;p.(Glu209Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 495141; OMIM: 610423.0001; PMID: 29656858) - PS4.This variant is not present in population databases (rs1555408401, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 29656858) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
PS2_very_strong, PS3, PS4, PM2
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.23; 3Cnet: 0.20). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000495141). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29656858). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29656858). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS3, PM1, PM2, PP3, PP5
Comment:
Published functional studies demonstrate an impaired interaction between PACS2 and related proteins (Olson et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28628100, 29656858, 28867141, 28135719, 30684285, 32416568, 32166392, 28191890, 30290155, 30904718, 31231135, 31036916, 25741868, 31130284, 34489640, 33243487, 33240318, 33461828, 33004838)
Comment:
A Heterozygous Missense variant c.625G>A in Exon 6 of the PACS2 gene that results in the amino acid substitution p.Glu209Lys was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variation ID: 495141). The variant has been previously reported for Developmental and epileptic encephalopathy by Olson HE, et al., 2018. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function (Olson HE, et al., 2018). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Comment:
BP4, PM2, PS2_very_strong, PS4
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 209 of the PACS2 protein (p.Glu209Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PACS2-related conditions (PMID: 29656858). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 495141). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PS2_VSTR,PS4,PS3_SUP,PM2_SUP
Comment:
PACS2: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function has been suggested (PMID: 29656858). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variability of clinical severity has been reported in a family (PMID: 35770754). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in many clinical testing laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The PACS2 c.625G>A variant is predicted to result in the amino acid substitution p.Glu209Lys. This variant has been documented in a large number of cases as a recurrent de novo cause of disease and the defining pathogenic variant in PACS2 (see for example, Olson et al. 2018. PubMed ID: 30290155). In vitro analysis in the Olson study indicated that this variant disrupts autoregulation and companion protein interactions. This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
| First reported case of an inherited PACS2 pathogenic variant with variable expression. | Cesaroni E | Epileptic disorders : international epilepsy journal with videotape | 2022 | PMID: 35770754 |
| Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network. | Denommé-Pichon AS | European journal of human genetics : EJHG | 2022 | PMID: 34782754 |
| Clinical variations of epileptic syndrome associated with PACS2 variant. | Mizuno T | Brain & development | 2021 | PMID: 33243487 |
| A further contribution to the delineation of epileptic phenotype in PACS2-related syndrome. | Terrone G | Seizure | 2020 | PMID: 32416568 |
| Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. | Bruel AL | European journal of human genetics : EJHG | 2019 | PMID: 31231135 |
| Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants. | Lecoquierre F | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31036916 |
| Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation. | Li J | Gene | 2019 | PMID: 30904718 |
| A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis. | Olson HE | American journal of human genetics | 2018 | PMID: 30290155 |
| A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis. | Olson HE | American journal of human genetics | 2018 | PMID: 29656858 |
| Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes. | Lelieveld SH | American journal of human genetics | 2017 | PMID: 28867141 |
| Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. | Geisheker MR | Nature neuroscience | 2017 | PMID: 28628100 |
| Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. | Kosmicki JA | Nature genetics | 2017 | PMID: 28191890 |
| Prevalence and architecture of de novo mutations in developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2017 | PMID: 28135719 |
| SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases. | Choquet K | European journal of human genetics : EJHG | 2016 | PMID: 26626314 |
| Early-onset optic neuropathy as initial clinical presentation in SPG7. | Marcotulli C | Journal of neurology | 2014 | PMID: 25034272 |
| Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort. | Yoon G | Neurogenetics | 2013 | PMID: 23733235 |
| Functional evaluation of paraplegin mutations by a yeast complementation assay. | Bonn F | Human mutation | 2010 | PMID: 20186691 |
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Record last updated Nov 25, 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.