NM_002087.4(GRN):c.328C>T (p.Arg110Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 1, 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:: RCV000084436.28

Allele description [Variation Report for NM_002087.4(GRN):c.328C>T (p.Arg110Ter)]

NM_002087.4(GRN):c.328C>T (p.Arg110Ter)

Gene:

GRN:granulin precursor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_002087.4(GRN):c.328C>T (p.Arg110Ter)

HGVS:

NC_000017.11:g.44349730C>T
NG_007886.1:g.9608C>T
NM_002087.4:c.328C>TMANE SELECT
NP_002078.1:p.Arg110Ter
LRG_661t1:c.328C>T
LRG_661:g.9608C>T
NC_000017.10:g.42427098C>T
NM_002087.2:c.328C>T
NM_002087.3:c.328C>T

Protein change:

R110*

Links:

dbSNP: rs63750411

NCBI 1000 Genomes Browser:

rs63750411

Molecular consequence:

NM_002087.4:c.328C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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
SCV000116572	VIB Department of Molecular Genetics, University of Antwerp	no classification provided	not provided	unknown	not provided
SCV000779672	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 21, 2022)	germline	clinical testing	Citation Link,
SCV001250430	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2023)	germline	clinical testing	Citation Link,
SCV001475245	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 11, 2020)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 31122931, 30528841, 25546130, 30279455, 29614680, 25525159, 17698705, 18245784, 20142524, 22312439, 23117491, 26467025
SCV005198422	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism.

Götzl JK, Brendel M, Werner G, Parhizkar S, Sebastian Monasor L, Kleinberger G, Colombo AV, Deussing M, Wagner M, Winkelmann J, Diehl-Schmid J, Levin J, Fellerer K, Reifschneider A, Bultmann S, Bartenstein P, Rominger A, Tahirovic S, Smith ST, Madore C, Butovsky O, Capell A, et al.

EMBO Mol Med. 2019 Jun;11(6). doi: 10.15252/emmm.201809711.

PubMed [citation]

PMID:: 31122931
PMCID:: PMC6554672

Genetic analysis of neurodegenerative diseases in a pathology cohort.

Blauwendraat C, Pletnikova O, Geiger JT, Murphy NA, Abramzon Y, Rudow G, Mamais A, Sabir MS, Crain B, Ahmed S, Rosenthal LS, Bakker CC, Faghri F, Chia R, Ding J, Dawson TM, Pantelyat A, Albert MS, Nalls MA, Resnick SM, Ferrucci L, Cookson MR, et al.

Neurobiol Aging. 2019 Apr;76:214.e1-214.e9. doi: 10.1016/j.neurobiolaging.2018.11.007. Epub 2018 Nov 17.

PubMed [citation]

PMID:: 30528841
PMCID:: PMC6391207

See all PubMed Citations (13)

Details of each submission

From VIB Department of Molecular Genetics, University of Antwerp, SCV000116572.1

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

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

From GeneDx, SCV000779672.4

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

Description

Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Also reported in an individual with a clinical diagnosis of posterior cortical atrophy with visual deficits, apperceptive visual agnosia, and occipital cortical atrophy (Caroppo et al., 2015); This variant is associated with the following publications: (PMID: 25525159, 29614680, 17698705, 30528841, 28749476, 30279455, 22312439, 25546130)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001250430.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

GRN: PVS1, PM2

#	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		2	not provided	not provided	not provided

From Athena Diagnostics, SCV001475245.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198422.1

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

#	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: Oct 20, 2024

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