NM_022726.4:c.512T>C

Variant names:

• chr6-79921654-A-G
• rs1554162301
• NM_022726.4:c.512T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_022726.4(ELOVL4):​c.512T>C​(p.Ile171Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I171L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELOVL4 NM_022726.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.46
• Publications: 6 publications found

Genes affected

ELOVL4 (HGNC:14415): (ELOVL fatty acid elongase 4) This gene encodes a membrane-bound protein which is a member of the ELO family, proteins which participate in the biosynthesis of fatty acids. Consistent with the expression of the encoded protein in photoreceptor cells of the retina, mutations and small deletions in this gene are associated with Stargardt-like macular dystrophy (STGD3) and autosomal dominant Stargardt-like macular dystrophy (ADMD), also referred to as autosomal dominant atrophic macular degeneration. [provided by RefSeq, Jul 2008]

ELOVL4 Gene-Disease associations (from GenCC):

• Stargardt disease 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• spinocerebellar ataxia type 34

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity ELOV4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_022726.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-79921655-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3337077.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant 6-79921654-A-G is Pathogenic according to our data. Variant chr6-79921654-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 435057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022726.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELOVL4	NM_022726.4	MANE Select	c.512T>C	p.Ile171Thr	missense	Exon 4 of 6	NP_073563.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELOVL4	ENST00000369816.5	TSL:1 MANE Select	c.512T>C	p.Ile171Thr	missense	Exon 4 of 6	ENSP00000358831.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 34 Pathogenic:2

Jul 23, 2025

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a missense, heterozygous variant NM_022726.4:c.512T>C p.(Ile171Thr) in the gene ELOVL4. This variant is absent from the database gnomAD (v4.1.0). In silico prediction scores are discordant regarding a deleterious effect. The affected amino acid is conserved and located within a functional protein domain (ELO). This variant has been reported as pathogenic/likely pathogenic in ClinVar (2*) and in LOVD. Pathogenic variants in ELOVL4 are responsible for several phenotypes, including spinocerebellar ataxia type 34 with autosomal dominant inheritance (OMIM #133190). This variant has been described in the literature in a family in which affected individuals presented with slowly progressive cerebellar ataxia, with onset between 38 and 57 years. In some family members, pigmentary retinopathy, ocular movement abnormalities, and pyramidal signs were also reported (PMID: 31750392). According to current evidence, this variant is considered pathogenic (class 5, according to ACMG criteria).

Jun 06, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Jul 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 435057). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the ELOVL4 protein (p.Ile171Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia and retinal disease (PMID: 28559085, 31692161, 31750392). It has also been observed to segregate with disease in related individuals.

May 07, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32780351, 33655653, 33816655, 31692161, 28559085, 29915382, 34689836, 34227061, 31750392, 34839010, 33556440, 36464075, 36696030, 36339301, 36748939, 37199746, 38850484, 39104105)

Stargardt disease 3;C1851481:Spinocerebellar ataxia type 34;C3280856:Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome Pathogenic:1

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.014	D
Polyphen		0.94	P
Vest4		0.82
MutPred		0.57		Loss of stability (P = 0.0175)
MVP		0.26
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.83
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554162301; hg19: chr6-80631371;