rs63749877

Positions:

• chr17-44351138-CCTCA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002087.4(GRN):​c.813_816delCACT​(p.Thr272fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRN NM_002087.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.49

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

GRN (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44351138-CCTCA-C is Pathogenic according to our data. Variant chr17-44351138-CCTCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 16020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44351138-CCTCA-C is described in Lovd as [Likely_pathogenic]. Variant chr17-44351138-CCTCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4	c.813_816delCACT	p.Thr272fs	frameshift_variant	8/13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.813_816delCACT	p.Thr272fs	frameshift_variant	8/13	1	NM_002087.4	ENSP00000053867.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 10, 2024	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2023	This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with FTLD-TDP or neuronal ceroid lipofuscinosis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Neuronal ceroid lipofuscinosis 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 08, 2012

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16020). This premature translational stop signal has been observed in individuals with autosomal dominant frontotemporal dementia and autosomal recessive neuronal ceroid lipofuscinosis (PMID: 18245784, 20947212, 21891869, 22127750, 22608501). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr272Serfs*10) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). -

Primary progressive aphasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 08, 2012

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63749877; hg19: chr17-42428506;