rs121918165

Positions:

chr6-79493636-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001122769.3(LCA5):c.835C>T(p.Gln279*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

LCA5
NM_001122769.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 2.58

Variant links:

Genes affected

LCA5 (HGNC:31923): (lebercilin LCA5) This gene encodes a protein that is thought to be involved in centrosomal or ciliary functions. Mutations in this gene cause Leber congenital amaurosis type V. Alternatively spliced transcript variants are described. [provided by RefSeq, Oct 2009]

LCA5 links:

ENSG00000231533 (HGNC:):

ENSG00000231533 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-79493636-G-A is Pathogenic according to our data. Variant chr6-79493636-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-79493636-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCA5	NM_001122769.3 linkuse as main transcript	c.835C>T	p.Gln279*	stop_gained	4/8	ENST00000369846.9	NP_001116241.1	Q86VQ0A0A384MDJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LCA5	ENST00000369846.9 linkuse as main transcript	c.835C>T	p.Gln279*	stop_gained	4/8	1	NM_001122769.3	ENSP00000358861.4	Q86VQ0
LCA5	ENST00000392959.5 linkuse as main transcript	c.835C>T	p.Gln279*	stop_gained	5/9	1		ENSP00000376686.1	Q86VQ0
LCA5	ENST00000467898.3 linkuse as main transcript	c.835C>T	p.Gln279*	stop_gained	4/7	5		ENSP00000474463.1	S4R3K6
ENSG00000231533	ENST00000652956.1 linkuse as main transcript	n.469+12196G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251064

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1461098

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000410

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 5

Pathogenic:7Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The LCA5 c.835C>T (p.Gln279Ter) variant is a stop-gained variant that is described in four studies, in which it was found in a homozygous state in five patients with Leber congenital amaurosis (LCA) and in a compound heterozygous state in three patients with LCA (den Hollander et al. 2007; Jacobson et al. 2009; MacKay et al. 2013; Farwell et al. 2015). The variant was absent from 180 total controls but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies by Boldt et al. (2011) showed that the p.Gln279Ter variant resulted in a total loss of the protein interactions shown by wild type libercilin with the intraflagellar transport (IFT) machinery. IFT-dependent protein transport is an evolutionarily conserved basic mechanism found in all cilia. The variant also caused a loss of additional protein binding capabilities. Based on the collective evidence, the p.Gln279Ter variant is classified as pathogenic for Leber congenital amaurosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The LCA5 c.835C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 22, 2022	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LCA5: PVS1, PM3:Strong, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2024	Published functional studies demonstrate a total loss of protein interaction with intraflagellar transport machinery (PMID: 21606596); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32579692, 25525159, 31456290, 31964843, 34906470, 19503738, 25356970, 21606596, 38219857, 17546029, 23946133) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Gln279*) in the LCA5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LCA5 are known to be pathogenic (PMID: 17546029, 23946133). This variant is present in population databases (rs121918165, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis (PMID: 17546029, 23946133). ClinVar contains an entry for this variant (Variation ID: 968). For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2013

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

Vest4

0.37

GERP RS

5.6

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over