rs587777598

Positions:

• chr6-79921662-C-G
• chr6-79921662-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The ENST00000369816.5(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 ENST00000369816.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity ELOV4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000369816.5
• 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	Protein	UniProt
ELOVL4	NM_022726.4	c.504G>C	p.Leu168Phe	missense_variant	4/6	ENST00000369816.5	NP_073563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELOVL4	ENST00000369816.5	c.504G>C	p.Leu168Phe	missense_variant	4/6	1	NM_022726.4	ENSP00000358831	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.71
Sift	Benign	0.090	T
Sift4G	Benign	0.097	T
Polyphen		0.87	P
Vest4		0.67
MutPred		0.55		Loss of sheet (P = 0.0817);
MVP		0.23
MPC		0.97
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.49
gMVP		0.83

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: rs587777598; hg19: chr6-80631379;