Neurodegenerative disorders, adult onset

Gene: GLT8D1

I don't know

Comment on list classification: This gene should be rated amber despite having large number of cases and some functional data (zebrafish motor deficits, neuronal cell morphology changes, enzyme activity loss). This is because several reported variants were excluded from scoring due to population frequencies too high to be consistent with disease, gene-wide burden analysis shows no significant ALS association once the exon 4 cluster is excluded, and several cases with p.Arg92Cys variant also co-carrying ARPP21 variant. In addition, this gene is rated as 'Limited' in ClinGen for ALS phenotype.

Created: 17 Aug 2026, 12:08 p.m. | Last Modified: 17 Aug 2026, 12:08 p.m.

Panel Version: 9.7

PMID:30811981 (2019) reported the identification of five potential causal variants via exome-sequencing in two related individuals with autosomal dominant amyotrophic lateral sclerosis (ALS). Another family member developed unilateral weakness and upper motor neuron dysfunction suggestive of ALS despite detailed neurological investigation not fulfilling El-Escorial diagnostic criteria, but no alternative cause being identified. Screening this individual for the five candidate mutations revealed only c.274C>T (p.Arg92Cys) in GLT8D1 gene and c.1586C>T (p.Pro529Leu) variant in ARPP21 gene.

Targeted sequencing in 103 familial and young sporadic ALS cases identified five additional patients carrying two missense variants within GLT8D1: the p.Arg92Cys variant identified in the index pedigree in four patients (three of them also had p.Pro529Leu in ARPP21) and c.232C>A (p.Gly78Trp) in one (no variant in ARPP21 gene). Sequencing of an international ALS cohort confirmed significant ALS-association with genetic variation in exon 4 of GLT8D1 in familial ALS patients, with p.Arg92Cys variant identified without p.Pro529Leu variant in ARPP21 gene in two additional patients. GLT8D1 p.Arg92Cys is present in 222 alleles and p.Gly78Trp is present in 10 alleles in gnomAD v4.1.1 whereas ARPP21 p.Pro529Leu is present in only 8 alleles.

Burden analysis showed there is no significant ALS-association within GLT8D1 when exon 4 is excluded. There is also functional evidence available including impaired enzyme activity, cytotoxicity, and motor deficits in GLT8D1 Knock Down in zebrafish embryos.

PMID:33581933 (2021) reported a cohort of 977 Chinese sporadic ALS (sALS) cases and 47 Chinese familial ALS (fALS) cases that underwent whole-exome sequencing. A likely pathogenic heterozyous variant in exon 4 ( c.233G>A/ p.Gly78Ala) was identified in a fALS case. This variant is present in 17 alleles in gnomAD v4.1.1 (although none in East Asian population). Four additional rare missense variants — p.V291I (fALS, pedigree unavailable — affected relative died), p.H24R (2 sALS patients), p.R255Q (1 sALS), p.G281S (1 sALS) — all classified as VUS due to lack of cosegregation and/or benign-to-tolerated in silico predictions.

Burden analysis in sALS cohort showed that there is no significant enrichment of rare GLT8D1 variants versus gnomAD East Asian controls at either whole-gene level (4 variants/1,410 combined sALS cases vs 25 variants/9,766 gnomAD controls) or exon 4–specific level (0 variants in sALS vs 3 in controls).

PMID:34746377 (2021) reported Sanger sequencing in a cohort of patients with ALS, of which a novel heterozygous variant in GLT8D1 gene (c.870C>G/ p.Ile290Met) was identified in a single patient with spinal-onset familial ALS. This variant is not found in gnomAD v4.1.1. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 17 August 2026), but associated with 'Limited' rating for amyotrophic lateral sclerosis (MONDO:0004976) by Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004967)

Created: 17 Aug 2026, 11:52 a.m. | Last Modified: 17 Aug 2026, 11:58 a.m.

Panel Version: 9.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
amyotrophic lateral sclerosis, MONDO:0004976

Publications

• 30811981
• 33581933
• 34746377

I don't know

PMID:30811981 - p.R92C in GLT8D1 was reported to be associated with ALS. However, p.P529L in ARPP21 was identified in many of the same patients in this study.

GLT8D1 p.R92C is present in 222 alleles in gnomAD v4.1.1 (https://gnomad.broadinstitute.org/variant/3-52697776-G-A?dataset=gnomad_r4) whereas ARPP21 p.P529L is present in only 8 (https://gnomad.broadinstitute.org/variant/3-35792484-C-T?dataset=gnomad_r4)

ARPP21 p.P529L has also been published in two additional papers associated with ALS (PMID: 38960585, 41917433)

Created: 16 Apr 2026, 3:43 p.m. | Last Modified: 16 Apr 2026, 3:43 p.m.

Panel Version: 8.21

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 30811981
• 38960585
• 41917433

I don't know

The association between GLT8D1 variants and familial amyotrophic lateral sclerosis (MONDO:0005144) has been set to Limited by the Amyotrophic Lateral Sclerosis Spectrum Disorders Expert Panel in ClinGen (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a2c4f919-ccb5-4d9f-a604-5ed19e19057e-2022-11-08T170000.000Z?page=1&size=25&search=) If this classification is changed in future this may be relevant to the rating of this gene in PanelApp.

Created: 18 Apr 2023, 11:31 a.m. | Last Modified: 18 Apr 2023, 11:31 a.m.

Panel Version: 4.20

Green List (high evidence)

14 ALS cases with heterozygous missense (10 cases with p.R92C), and supporting in vitro functional assays and zebrafish model.
Sources: Expert list

Created: 27 Sep 2020, 11:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Amyotrophic lateral sclerosis

Publications

• 30811981

Variants in this GENE are reported as part of current diagnostic practice