Hereditary ataxia, adult onset

Gene: ELOVL5

Green List (high evidence)

Comment on list classification: There are now 3 unrelated families reported in literature with 3 unique monoallelic ELOVL5 missense variants, affected by adult-onset spinocerebellar ataxia. There is also a fourth pedigree, reported in PMID: 32314013, with a likely benign variant with a high allele frequency in gnomAD (not counted). Based on available evidence, this gene can be promoted to Green at the next update.

Created: 14 Aug 2026, 4:23 p.m. | Last Modified: 14 Aug 2026, 4:23 p.m.

Panel Version: 9.6

PMID: 40940404 Watanabe et al., 2025
Patient 3 - Japanese male, het for ELOVL5 c.179 C > T, p.S60F variant. This variant has 2 alleles reported in gnomAD v4.1.1, no homozygotes. Patient exhibited slowly progressive SCA with dysarthria, limb ataxia, and truncal ataxia, but no spasticity. Disease onset was at 37 years old; he became wheelchair dependent at 53 yrs. Brain stem and cerebellar atrophy noted. He had an additional feature of bladder and rectal disturbances. Family history: Mother, sibling, maternal uncle, and maternal aunt affected. No family genetic testing done.

PMID: 32314013 Gazulla et al., 2020
Family with 5 affected individuals with gait ataxia and intermittent diplopia. Vestibular impairment and sensory neuronopathy were also noted. WES demonstrated a heterozygous variant in ELOVL5, c.779A>G (p.Tyr260Cys), in four tested patients. Disease onset was during 5th and 6th decades. Variant is LIKELY BENIGN in ClinVar, reported in gnomAD v4.1.1 with MAF = 0.001286 (European Non-Finnish population), including 1 homozygote - way too common for a dominant disease.

PMID: 25065913 DiGregorio et al., 2014
Three SCA-affected Italian families (2 have confirmed shared ancestry, third may be more distantly related or same variant arose spontaneously). ELOVL5 heterozygous variant c.689G>T, p.Gly230Val cosegregated with disease. Variant is not present in gnomAD v4.1.1. Disease onset was around 34-45 years of age, with slowly progressive symptoms.
Another heterozygous missense variant, ELOVL5 c.214C>G, p.Leu72Val, was detected in a French family with SCA. Variant is reported in 1 heterozygote in gnomAD v4.1.1. The female proband had ataxia with age of onset 51 years.

FUNCTIONAL EVIDENCE:
PMID: 37199746 Ferrero et al., 2023 - same research group as PMID: 25065913
Functional evidence showing that ELOVL5 c.689G>T p.Gly230Val is proteotoxic - mouse cortical neurons were transduced with lentiviruses expressing GFP and an ELOVL5 protein (wild type or mutant). Wild-type ELOVL5 did not affect neuronal viability whereas expression of p.G230V decreased neuronal viability by 10%.

This gene is associated with AD Spinocerebellar ataxia 38, MIM:615957 (OMIM accessed 14th Aug 2026).

Created: 14 Aug 2026, 3:51 p.m. | Last Modified: 14 Aug 2026, 4:25 p.m.

Panel Version: 9.10

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 38, OMIM:615957; spinocerebellar ataxia type 38, MONDO:0014417

Publications

• 25065913
• 32314013
• 37199746
• 40940404

Red List (low evidence)

On Oxford panel. Only 2 DM in HGMD published by same group

Created: 27 Apr 2019, 7:39 p.m.

I don't know

Downgraded rating from Green to Amber. As discussed with the GMS Neurology Specialist Test Group webex call 26th July 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber

Created: 1 Aug 2019, 3:43 p.m. | Last Modified: 1 Aug 2019, 3:43 p.m.

Panel Version: 1.188

Review and rating submitted by James Polke (Neurogenetics Laboratory, Institute of Neurology, London) on behalf of London North GLH for GMS Neurology specialist test group

Created: 27 Apr 2019, 8:55 p.m.

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.

Created: 15 Apr 2019, 10:21 a.m.

Green List (high evidence)

At least four families in literature, functional evidence for gene and variants reported in original paper

Created: 15 Apr 2019, 10:06 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 38, 615957

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments

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