Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021180, PMID:9860301). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000430.4(PAFAH1B1):c.162del (p.Lys54fs)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000430.4(PAFAH1B1):c.162del (p.Lys54fs)
Variation ID: 21180 Accession: VCV000021180.18
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17p13.3 17: 2666053 (GRCh38) [ NCBI UCSC ] 17: 2569347 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Sep 16, 2024 Aug 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000430.4:c.162del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000421.1:p.Lys54fs frameshift NC_000017.11:g.2666060del NC_000017.10:g.2569354del NG_009799.1:g.77432del - Protein change
- K54fs
- Other names
- -
- Canonical SPDI
- NC_000017.11:2666052:AAAAAAAA:AAAAAAA
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| PAFAH1B1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
534 | 619 | |
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
|
May 4, 2022 | RCV000020302.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 13, 2024 | RCV000255298.9 |
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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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lissencephaly due to LIS1 mutation
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058998.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported … (more)
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021180, PMID:9860301). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Narrow forehead (present) , Abnormal corpus callosum morphology (present) , Diminished movement (present) , EEG abnormality (present) , Failure to thrive (present) , Generalized hypotonia … (more)
Narrow forehead (present) , Abnormal corpus callosum morphology (present) , Diminished movement (present) , EEG abnormality (present) , Failure to thrive (present) , Generalized hypotonia (present) , Global developmental delay (present) , Hyporeflexia (present) , Lissencephaly (present) , Developmental regression (present) , Poor suck (present) , Progressive microcephaly (present) , Seizure (present) (less)
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Pathogenic
(Aug 28, 2017)
|
criteria provided, single submitter
Method: provider interpretation, clinical testing
|
Lissencephaly due to LIS1 mutation
Affected status: yes
Allele origin:
unknown
|
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804441.2
First in ClinVar: Nov 23, 2014 Last updated: Dec 11, 2022 |
Comment:
This 5 year old male with global developmental delays, seizure disorder, and subcortical band heterotopia was found to carry a variant in the PAFAH1B1 gene, … (more)
This 5 year old male with global developmental delays, seizure disorder, and subcortical band heterotopia was found to carry a variant in the PAFAH1B1 gene, also known as LIS1. The patient is mosaic for this variant, at an unknown level. A paternal sample is unavailable, so inheritance of the variant is unknown, but it is assumed to be de novo. The c.162delA variant has been reported multiple times previously in association with lissencephaly (Sakamoto et al., 1998; de Wit et al., 2011; Dobyns and Das, 2014). Other researchers have identified patients who had subcortical band heterotopia that had somatic mosaicism for variants in the PAFAH1B1 gene (PMIDs: 10441340, 11502906, 14581661); their phenotypes were noted to be less severe than individuals not mosaic for the variants. (less)
Observation 1:
Clinical Features:
Global developmental delay (present) , Seizures (present) , Heterotopia (present)
Age: 0-9 years
Sex: male
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-07-06
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Seizures (present) , Heterotopia (present)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-07-06
Testing laboratory interpretation: Pathogenic
|
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Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002118385.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21180). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21180). This premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 9860301, 21410694). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys54Asnfs*15) in the PAFAH1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAFAH1B1 are known to be pathogenic (PMID: 1671808, 11115846, 14581661). (less)
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Pathogenic
(Aug 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322035.10
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Reported previously multiple times in association with lissencephaly (PMID: 9860301, 21410694, 20301752); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in … (more)
Reported previously multiple times in association with lissencephaly (PMID: 9860301, 21410694, 20301752); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21410694, 20301752, 11502906, 14581661, 10441340, 32005694, 36100855, 32906206, 9860301) (less)
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Pathogenic
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
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Lissencephaly 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000194363.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Lissencephaly due to LIS1 mutation
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517841.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
Comment:
Comment:
This 5 year old male with global developmental delays, seizure disorder, and subcortical band heterotopia was found to carry a variant in the PAFAH1B1 gene, also known as LIS1. The patient is mosaic for this variant, at an unknown level. A paternal sample is unavailable, so inheritance of the variant is unknown, but it is assumed to be de novo. The c.162delA variant has been reported multiple times previously in association with lissencephaly (Sakamoto et al., 1998; de Wit et al., 2011; Dobyns and Das, 2014). Other researchers have identified patients who had subcortical band heterotopia that had somatic mosaicism for variants in the PAFAH1B1 gene (PMIDs: 10441340, 11502906, 14581661); their phenotypes were noted to be less severe than individuals not mosaic for the variants.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21180). This premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 9860301, 21410694). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys54Asnfs*15) in the PAFAH1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAFAH1B1 are known to be pathogenic (PMID: 1671808, 11115846, 14581661).
Comment:
Reported previously multiple times in association with lissencephaly (PMID: 9860301, 21410694, 20301752); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21410694, 20301752, 11502906, 14581661, 10441340, 32005694, 36100855, 32906206, 9860301)
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:
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000021180, PMID:9860301). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This 5 year old male with global developmental delays, seizure disorder, and subcortical band heterotopia was found to carry a variant in the PAFAH1B1 gene, also known as LIS1. The patient is mosaic for this variant, at an unknown level. A paternal sample is unavailable, so inheritance of the variant is unknown, but it is assumed to be de novo. The c.162delA variant has been reported multiple times previously in association with lissencephaly (Sakamoto et al., 1998; de Wit et al., 2011; Dobyns and Das, 2014). Other researchers have identified patients who had subcortical band heterotopia that had somatic mosaicism for variants in the PAFAH1B1 gene (PMIDs: 10441340, 11502906, 14581661); their phenotypes were noted to be less severe than individuals not mosaic for the variants.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21180). This premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 9860301, 21410694). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys54Asnfs*15) in the PAFAH1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAFAH1B1 are known to be pathogenic (PMID: 1671808, 11115846, 14581661).
Comment:
Reported previously multiple times in association with lissencephaly (PMID: 9860301, 21410694, 20301752); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21410694, 20301752, 11502906, 14581661, 10441340, 32005694, 36100855, 32906206, 9860301)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Long-term follow-up of type 1 lissencephaly: survival is related to neuroimaging abnormalities. | de Wit MC | Developmental medicine and child neurology | 2011 | PMID: 21410694 |
| Mosaic mutations of the LIS1 gene cause subcortical band heterotopia. | Sicca F | Neurology | 2003 | PMID: 14581661 |
| LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ. | Leventer RJ | Neurology | 2001 | PMID: 11502906 |
| The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. | Cardoso C | Human molecular genetics | 2000 | PMID: 11115846 |
| Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1. | Pilz DT | Human molecular genetics | 1999 | PMID: 10441340 |
| Alteration of the LIS1 gene in Japanese patients with isolated lissencephaly sequence or Miller-Dieker syndrome. | Sakamoto M | Human genetics | 1998 | PMID: 9860301 |
| Clinical and molecular diagnosis of Miller-Dieker syndrome. | Dobyns WB | American journal of human genetics | 1991 | PMID: 1671808 |
Text-mined citations for rs113994198 ...
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.