rs386834252

chr6-79489163-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001122769.3(LCA5):c.1151del(p.Pro384GlnfsTer18) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P384P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LCA5 NM_001122769.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 1.23

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 51 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	UniProt
LCA5	NM_001122769.3	c.1151del	p.Pro384GlnfsTer18	frameshift_variant	7/8	ENST00000369846.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCA5	ENST00000369846.9	c.1151del	p.Pro384GlnfsTer18	frameshift_variant	7/8	1	NM_001122769.3	P1
LCA5	ENST00000392959.5	c.1151del	p.Pro384GlnfsTer18	frameshift_variant	8/9	1		P1
	ENST00000652956.1	n.469+7726del		intron_variant, non_coding_transcript_variant
LCA5	ENST00000467898.3	c.1151del	p.Pro384GlnfsTer18	frameshift_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250504 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135434

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: 11 AN: 1460812 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726748

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 5 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
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

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs386834252; hg19: chr6-80198880;