NM_005022.4(PFN1):c.350_351delinsGT (p.Glu117Gly) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 23, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000800637.16

Allele description [Variation Report for NM_005022.4(PFN1):c.350_351delinsGT (p.Glu117Gly)]

NM_005022.4(PFN1):c.350_351delinsGT (p.Glu117Gly)

Gene:

PFN1:profilin 1 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_005022.4(PFN1):c.350_351delinsGT (p.Glu117Gly)

HGVS:

NC_000017.11:g.4945972_4945973delinsAC
NG_012063.2:g.4882_4883delinsAC
NG_032945.1:g.8114_8115delinsGT
NM_001375991.1:c.*434_*435delinsGT
NM_005022.4:c.350_351delinsGTMANE SELECT
NP_005013.1:p.Glu117Gly
NP_005013.1:p.Glu117Gly
NC_000017.10:g.4849267_4849268delinsAC
NM_005022.2:c.350_351delinsGT
NM_005022.3:c.350_351delAAinsGT
NM_005022.3:c.350_351delinsGT

Protein change:

E117G

Links:

dbSNP: rs1597686012

NCBI 1000 Genomes Browser:

rs1597686012

Molecular consequence:

NM_001375991.1:c.*434_*435delinsGT - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_005022.4:c.350_351delinsGT - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000940366	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 23, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 23063648, 23141414, 23312802, 23634771, 23635659, 24309268, 25943890, 22801503, 24920614, 26056300, 27432186, 28040732, 35628504, 28492532
SCV001144913	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Jul 30, 2019)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 25499087, 26056300, 24309268, 26572741, 27432186, 23634771, 23635659, 24920614, 28459188, 22801503, 23312802, 23063648, 26467025
SCV001950522	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Benign (Sep 3, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000940366

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 23, 2023)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV001144913

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Jul 30, 2019)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV001950522

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Benign
(Sep 3, 2020)

germline

clinical testing

Citation Link

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

A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts.

Ingre C, Landers JE, Rizik N, Volk AE, Akimoto C, Birve A, Hübers A, Keagle PJ, Piotrowska K, Press R, Andersen PM, Ludolph AC, Weishaupt JH.

Neurobiol Aging. 2013 Jun;34(6):1708.e1-6. doi: 10.1016/j.neurobiolaging.2012.10.009. Epub 2012 Nov 8.

PubMed [citation]

PMID:: 23141414
PMCID:: PMC6591725

Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease.

Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R, Brown P, Ravenscroft T, van Blitterswijk M, Nicholson AM, DeTure M, Knopman DS, Josephs KA, Parisi JE, Petersen RC, Boylan KB, Boeve BF, Graff-Radford NR, Veltman JA, Gilissen C, Murray ME, Dickson DW, et al.

Acta Neuropathol. 2015 Jul;130(1):77-92. doi: 10.1007/s00401-015-1436-x. Epub 2015 May 6.

PubMed [citation]

PMID:: 25943890
PMCID:: PMC4470809

See all PubMed Citations (18)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000940366.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 117 of the PFN1 protein (p.Glu117Gly). 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 missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD) (PMID: 22801503, 23063648, 23141414, 23312802, 23634771, 23635659, 24309268, 25943890). ClinVar contains an entry for this variant (Variation ID: 646360). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PFN1 function (PMID: 22801503, 24920614, 26056300, 27432186, 28040732, 35628504). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From Athena Diagnostics, SCV001144913.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

#	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

From GeneDx, SCV001950522.2

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

Description

This variant is associated with the following publications: (PMID: 22801503, 25943890, 23634771, 23063648, 26226631, 25499087, 23312802, 23141414)

#	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

Last Updated: Sep 29, 2024

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