NM_002087.4(GRN):c.530G>A (p.Arg177His) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 19, 2022
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:: RCV001907975.4

Allele description [Variation Report for NM_002087.4(GRN):c.530G>A (p.Arg177His)]

NM_002087.4(GRN):c.530G>A (p.Arg177His)

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.530G>A (p.Arg177His)

HGVS:

NC_000017.11:g.44350509G>A
NG_007886.1:g.10387G>A
NM_002087.4:c.530G>AMANE SELECT
NP_002078.1:p.Arg177His
LRG_661:g.10387G>A
NC_000017.10:g.42427877G>A

Protein change:

R177H

Links:

dbSNP: rs753441122

NCBI 1000 Genomes Browser:

rs753441122

Molecular consequence:

NM_002087.4:c.530G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Synonyms:: FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS; FTLD-TDP, GRN-RELATED; Frontotemporal dementia, ubiquitin-positive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011842; MedGen: C1843792; Orphanet: 100070; Orphanet: 282; OMIM: 607485

Name:: Neuronal ceroid lipofuscinosis 11
Synonyms:: GRN-Related Neuronal Ceroid-Lipofuscinosis
Identifiers:: MONDO: MONDO:0013866; MedGen: C3539123; Orphanet: 314629; Orphanet: 79262; OMIM: 614706

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002147359	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17950702, 28492532
SCV002816390	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002147359

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 19, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002816390

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 1, 2021)

unknown

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings.

López de Munain A, Alzualde A, Gorostidi A, Otaegui D, Ruiz-Martínez J, Indakoetxea B, Ferrer I, Pérez-Tur J, Sáenz A, Bergareche A, Barandiarán M, Poza JJ, Zabalza R, Ruiz I, Urtasun M, Fernández-Manchola I, Olasagasti B, Espinal JB, Olaskoaga J, Ruibal M, Moreno F, Carrera N, et al.

Biol Psychiatry. 2008 May 15;63(10):946-52. Epub 2007 Oct 22.

PubMed [citation]

PMID:: 17950702

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002147359.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1372270). This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 17950702). This variant is present in population databases (rs753441122, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 177 of the GRN protein (p.Arg177His).

#	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 Fulgent Genetics, Fulgent Genetics, SCV002816390.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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