rs587777598
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_022726.4(ELOVL4):c.504G>C(p.Leu168Phe) variant causes a missense 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L168L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
ELOVL4
NM_022726.4 missense
NM_022726.4 missense
Scores
3
6
10
Clinical Significance
Conservation
PhyloP100: 0.988
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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;
PP5
?
Variant 6-79921662-C-G is Pathogenic according to our data. Variant chr6-79921662-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 143056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELOVL4 | NM_022726.4 | c.504G>C | p.Leu168Phe | missense_variant | 4/6 | ENST00000369816.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELOVL4 | ENST00000369816.5 | c.504G>C | p.Leu168Phe | missense_variant | 4/6 | 1 | NM_022726.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
ELOVL4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2023 | Variant summary: ELOVL4 c.504G>C (p.Leu168Phe) results in a non-conservative amino acid change located in the third transmembrane domain (Cadieux-Dion_214) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.504G>C has been reported in the literature as segregating with disease in multiple individuals from a large French Canadian family affected with features of ELOVL4-Related Disorder presenting as Autosomal Dominant Spinocerebellar Ataxia and Erythrokeratodermia (Cadieux-Dion_2014 overlapping with Beaudin_2020). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function demonstrated mislocalization of the ELOVL4 protein in dermal fibroblasts from affected individuals (Beaudin_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32211516, 24566826). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Spinocerebellar ataxia type 34 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
Stargardt disease 3;C1851481:Spinocerebellar ataxia type 34;C3280856:Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 17, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of sheet (P = 0.0817);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at