rs121918244

chr3-121781772-G-A

Variant summary

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

The NM_001023570.4(IQCB1):c.1381C>T(p.Arg461Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,482 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: IQCB1 NM_001023570.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.27

Genes affected

IQCB1 (HGNC:28949): (IQ motif containing B1) This gene encodes a nephrocystin protein that interacts with calmodulin and the retinitis pigmentosa GTPase regulator protein. The encoded protein has a central coiled-coil region and two calmodulin-binding IQ domains. It is localized to the primary cilia of renal epithelial cells and connecting cilia of photoreceptor cells. The protein is thought to play a role in ciliary function. Defects in this gene result in Senior-Loken syndrome type 5. Alternative splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Jan 2016]

ACMG classification

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 3-121781772-G-A is Pathogenic according to our data. Variant chr3-121781772-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-121781772-G-A is described in Lovd as [Pathogenic]. Variant chr3-121781772-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQCB1	NM_001023570.4	c.1381C>T	p.Arg461Ter	stop_gained	13/15	ENST00000310864.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQCB1	ENST00000310864.11	c.1381C>T	p.Arg461Ter	stop_gained	13/15	1	NM_001023570.4	P1
IQCB1	ENST00000349820.10	c.982C>T	p.Arg328Ter	stop_gained	10/12	1
IQCB1	ENST00000393650.7	c.*359C>T		3_prime_UTR_variant, NMD_transcript_variant	12/14	5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151978 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251372 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461388 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 727012

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152094 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74354

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000862 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Senior-Loken syndrome 5 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 07, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Published functional studies demonstrate the mutant protein is incompetent in binding to Cep290, mislocalized, and unable to rescue ciliogenesis (Barbelanne et al., 2013); 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: 21866095, 25525159, 30586318, 23446637, 15723066, 21220633, 23847139, 31456290, 32581362, 33512896, 31589614, 36426739, 33535056, 28041643, 20881296, 28559085) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.1381C>T (p.R461*) alteration, located in exon 13 (coding exon 11) of the IQCB1 gene, consists of a C to T substitution at nucleotide position 1381. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 461. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (18/282708) total alleles studied. The highest observed frequency was 0.154% (16/10370) of Ashkenazi Jewish alleles. This variant has been reported homozygous or compound heterozygous in multiple individuals with features consistent with IQCB1-related Senior-Loken syndrome (Otto, 2005; Otto, 2008; Chaki, 2011; Cideciyan, 2011; Estrada-Cuzcano, 2011; Stone, 2011; Halbritter, 2012; Coppieters, 2014; Wang, 2013; Rishi, 2021). One functional study has demonstrated that p.R461* disrupts protein-protein interactions with Cep290, causes mislocalization, and inhibits cilia formation in cells (Barbelanne, 2013). Based on the available evidence, this alteration is classified as pathogenic. -

Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

This sequence change creates a premature translational stop signal (p.Arg461*) in the IQCB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQCB1 are known to be pathogenic (PMID: 15723066, 21901789, 23559409, 28041643). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Leber congenital amaurosis and/or Senior-Loken syndrome (PMID: 15723066, 20881296, 21220633, 21245082, 21866095, 23188109, 23847139, 24625443). ClinVar contains an entry for this variant (Variation ID: 1830). For these reasons, this variant has been classified as Pathogenic. -

IQCB1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2023

The IQCB1 c.1381C>T variant is predicted to result in premature protein termination (p.Arg461*). This variant has been reported in homozygous or compound heterozygous states in multiple individuals with Senior-Loken syndrome, Leber congenital amaurosis and/or other retinal diseases (Otto et al. 2005. PubMed ID: 15723066; Estrada-Cuzcano et al. 2011. PubMed ID: 20881296; Stone et al. 2017. PubMed ID: 28559085. Table S1). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-121500619-G-A). However, the frequency data for this variant is considered unreliable since metrics indicate poor data quality at this position in the gnomAD database. Nonsense variants in IQCB1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Renal dysplasia and retinal aplasia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A;A
Vest4		0.065
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs121918244; hg19: chr3-121500619;