chr6-79916817-A-C

Variant names:

• chr6-79916817-A-C
• rs1131692036
• NM_022726.4:c.736T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_022726.4(ELOVL4):​c.736T>G​(p.Trp246Gly) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ELOVL4 NM_022726.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32
• Publications: 21 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 6-79916817-A-C is Pathogenic according to our data. Variant chr6-79916817-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 430572.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELOVL4	NM_022726.4	c.736T>G	p.Trp246Gly	missense_variant	Exon 6 of 6	ENST00000369816.5	NP_073563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELOVL4	ENST00000369816.5	c.736T>G	p.Trp246Gly	missense_variant	Exon 6 of 6	1	NM_022726.4	ENSP00000358831.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 34 Pathogenic:1

Jun 30, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Dec 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: impaired production of very long chain saturated fatty acids (VLC-SFA), reduced long-term potentiation at parallel fiber synapses as well as long-term depression at climbing fiber synapses onto Purkinje cells, and impaired motor function in rat models (Agbaga et al., 2020; Nagaraja et al., 2021); Although W246G did not affect retinal Elovl4 expression and protein synthesis in rat models, it was proposed that the reduced production of VLC-SFA impaired synaptic transmission from photoreceptors to the inner retina (Agbaga et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26010696, 34689836, 32780351, 34227061) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.52
Sift	Benign	0.18	T
Sift4G	Benign	0.39	T
Polyphen		0.99	D
Vest4		0.86
MutPred		0.69		Gain of loop (P = 0.0121);
MVP		0.23
MPC		1.6
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.76
gMVP		0.89
Mutation Taster		=9/91	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: rs1131692036; hg19: chr6-80626534;