Variant chr6-79489163-TG-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001122769.3(LCA5):c.1151delC(p.Pro384fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

LCA5
NM_001122769.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 1.23

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:

LOC100506851 (HGNC:):

LOC100506851 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-79489163-TG-T is Pathogenic according to our data. Variant chr6-79489163-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-79489163-TG-T is described in Lovd as [Pathogenic]. Variant chr6-79489163-TG-T 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.1151delC	p.Pro384fs	frameshift_variant	7/8	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.1151delC	p.Pro384fs	frameshift_variant	7/8	1	NM_001122769.3	ENSP00000358861.4	Q86VQ0
LCA5	ENST00000392959.5 linkuse as main transcript	c.1151delC	p.Pro384fs	frameshift_variant	8/9	1		ENSP00000376686.1	Q86VQ0
LCA5	ENST00000467898.3 linkuse as main transcript	c.1151delC	p.Pro384fs	frameshift_variant	7/7	5		ENSP00000474463.1	S4R3K6
ENSG00000231533	ENST00000652956.1 linkuse as main transcript	n.469+7726delG		intron_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250504

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460812

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 5

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 03, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Leber congenital amaurosis

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: LCA5 c.1151delC (p.Pro384GlnfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and are associated with Leber Congenital Amaurosis in HGMD. The variant allele was found at a frequency of 4e-06 in 250504 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1151delC has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis/early-onset retinal degeneration and has been shown to segregate with disease (e.g., denHollander_2007, MacKay_2013, Li_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change creates a premature translational stop signal (p.Pro384Glnfs*18) in the LCA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 314 amino acid(s) of the LCA5 protein. This variant is present in population databases (rs386834252, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with LCA5-related retinal dystrophy (PMID: 17546029, 26352687). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 966). This variant disrupts a region of the LCA5 protein in which other variant(s) (p.Lys586*) have been determined to be pathogenic (PMID: 23946133, 27624628). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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