NM_000430.4(PAFAH1B1):c.162dup (p.Trp55fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 3, 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:: RCV000364082.6

Allele description [Variation Report for NM_000430.4(PAFAH1B1):c.162dup (p.Trp55fs)]

NM_000430.4(PAFAH1B1):c.162dup (p.Trp55fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

17p13.3

Genomic location:

Preferred name:

NM_000430.4(PAFAH1B1):c.162dup (p.Trp55fs)

HGVS:

NC_000017.11:g.2666060dup
NG_009799.1:g.77432dup
NM_000430.4:c.162dupMANE SELECT
NP_000421.1:p.Trp55fs
NC_000017.10:g.2569346_2569347insA
NC_000017.10:g.2569354dup
NC_000017.11:g.2666052_2666053insA
NM_000430.3:c.162dup
NM_000430.3:c.162dupA
p.Trp55Metfs*6

Protein change:

W55fs

Links:

dbSNP: rs113994198

NCBI 1000 Genomes Browser:

rs113994198

Molecular consequence:

NM_000430.4:c.162dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000329811	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 10, 2018)	germline	clinical testing	Citation Link,
SCV003442376	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 3, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9817918, 1671808, 11115846, 14581661, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329811

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 10, 2018)

germline

clinical testing

Citation Link,

SCV003442376

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 3, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation.

Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, Walsh CA, Barkovich AJ, Dobyns WB, Ledbetter DH, Ross ME.

Hum Mol Genet. 1998 Dec;7(13):2029-37.

PubMed [citation]

PMID:: 9817918

Clinical and molecular diagnosis of Miller-Dieker syndrome.

Dobyns WB, Curry CJ, Hoyme HE, Turlington L, Ledbetter DH.

Am J Hum Genet. 1991 Mar;48(3):584-94.

PubMed [citation]

PMID:: 1671808
PMCID:: PMC1682996

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000329811.6

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

Description

The c.162dupA pathogenic variant in the PAFAH1B1 gene has been reported previously as a de novo variant in an individual with isolated lissencephaly sequence (Pilz et al., 1998). The duplication causes a frameshift starting with codon Tryptophan 55, changes this amino acid to a Methionine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Trp55MetfsX6. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, it was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.

#	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 Invitae, SCV003442376.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is also known as LIS1 c.162insA. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21181). This premature translational stop signal has been observed in individual(s) with lissencephaly (PMID: 9817918). 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.Trp55Metfs*6) 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).

#	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: Apr 15, 2024

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