rs121918165

Variant names:

• chr6-79493636-G-A
• rs121918165
• NM_001122769.3:c.835C>T
• LCA5 p.Gln279*

Your query was ambiguous. Multiple possible variants found:

• chr6-79493636-G-A
• chr6-79493636-G-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000465592: 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. PMID:21746975" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q279Q) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 2.58
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• LCA5-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leber congenital amaurosis 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231533 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000465592: 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. PMID:21746975; SCV001805283: Published functional studies demonstrate a total loss of protein interaction with intraflagellar transport machinery (PMID: 21606596)
• PP5: Variant 6-79493636-G-A is Pathogenic according to our data. Variant chr6-79493636-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122769.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5	NM_001122769.3	MANE Select	c.835C>T	p.Gln279*	stop_gained	Exon 4 of 8	NP_001116241.1	A0A384MDJ7
	LCA5	NM_181714.4		c.835C>T	p.Gln279*	stop_gained	Exon 5 of 9	NP_859065.2	A0A384MDJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5	ENST00000369846.9	TSL:1 MANE Select	c.835C>T	p.Gln279*	stop_gained	Exon 4 of 8	ENSP00000358861.4	Q86VQ0
	LCA5	ENST00000392959.5	TSL:1	c.835C>T	p.Gln279*	stop_gained	Exon 5 of 9	ENSP00000376686.1	Q86VQ0
	LCA5	ENST00000467898.3	TSL:5	c.835C>T	p.Gln279*	stop_gained	Exon 4 of 7	ENSP00000474463.1	S4R3K6

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152138 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251064 AF XY: 0.000111

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000589 AC: 86 AN: 1461098 Hom.: 1 Cov.: 30 AF XY: 0.0000605 AC XY: 44 AN XY: 726896

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111422

Other (OTH) AF: 0.000232 AC: 14 AN: 60366

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.0000756

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Leber congenital amaurosis 5 (9)
3	-	-	Leber congenital amaurosis (3)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		2.6
Mutation Taster		=4/196	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121918165;

hg19: chr6-80203353;