NM_000430.4(PAFAH1B1):c.569-10T>C AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 7, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000494023.16

Allele description

NM_000430.4(PAFAH1B1):c.569-10T>C

Gene:

PAFAH1B1:platelet activating factor acetylhydrolase 1b regulatory subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.3

Genomic location:

Preferred name:

NM_000430.4(PAFAH1B1):c.569-10T>C

HGVS:

NC_000017.11:g.2672645T>C
NG_009799.1:g.84017T>C
NM_000430.4:c.569-10T>CMANE SELECT
NC_000017.10:g.2575939T>C
NM_000430.3:c.569-10T>C

Links:

dbSNP: rs113994202

NCBI 1000 Genomes Browser:

rs113994202

Molecular consequence:

NM_000430.4:c.569-10T>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000582158	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 7, 2023)	germline	clinical testing	Citation Link,
SCV000708127	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 11, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17664403, 11115846, 27891766 Citation Link,
SCV002160026	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11115846, 17664403, 27891766, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000582158

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 7, 2023)

germline

clinical testing

Citation Link,

SCV000708127

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Dec 11, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002160026

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 21, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene.

Cardoso C, Leventer RJ, Matsumoto N, Kuc JA, Ramocki MB, Mewborn SK, Dudlicek LL, May LF, Mills PL, Das S, Pilz DT, Dobyns WB, Ledbetter DH.

Hum Mol Genet. 2000 Dec 12;9(20):3019-28.

PubMed [citation]

PMID:: 11115846

Location and type of mutation in the LIS1 gene do not predict phenotypic severity.

Uyanik G, Morris-Rosendahl DJ, Stiegler J, Klapecki J, Gross C, Berman Y, Martin P, Dey L, Spranger S, Korenke GC, Schreyer I, Hertzberg C, Neumann TE, Burkart P, Spaich C, Meng M, Holthausen H, Adès L, Seidel J, Mangold E, Buyse G, Meinecke P, et al.

Neurology. 2007 Jul 31;69(5):442-7.

PubMed [citation]

PMID:: 17664403

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000582158.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Functional studies suggest c.569-10 T>C causes abnormal gene splicing (Philbert et al., 2017); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17664403, 11115846, 27891766, 29671837, 36100855)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000708127.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV002160026.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 27891766). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 21182). This variant has been observed in individual(s) with lissencephaly (PMID: 11115846, 17664403, 27891766). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the PAFAH1B1 gene. It does not directly change the encoded amino acid sequence of the PAFAH1B1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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