rs1131691667

Positions:

• chr8-71271835-G-A

Variant summary

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

The NM_000503.6(EYA1):​c.889C>T​(p.Arg297Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.54

Genes affected

EYA1 (HGNC:3519): (EYA transcriptional coactivator and phosphatase 1) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may play a role in the developing kidney, branchial arches, eye, and ear. Mutations of this gene have been associated with branchiootorenal dysplasia syndrome, branchiootic syndrome, and sporadic cases of congenital cataracts and ocular anterior segment anomalies. A similar protein in mice can act as a transcriptional activator. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2013]

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 8-71271835-G-A is Pathogenic according to our data. Variant chr8-71271835-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 429912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71271835-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6	c.889C>T	p.Arg297Ter	stop_gained	10/18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.889C>T	p.Arg297Ter	stop_gained	10/18	1	NM_000503.6	ENSP00000342626	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiootic syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

-

PVS1, PM2, PP3, PP4 -

EYA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

The EYA1 c.889C>T variant is predicted to result in premature protein termination (p.Arg297*). This variant was reported in multiple individuals with branchio-oto-renal syndrome (described as R265X, Rickard et al. 2000. PubMed ID: 10991693; described as R264X, Fukuda et al. 2001. PubMed ID: 11683347; Feng et al. 2021. PubMed ID: 34868248). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in EYA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Melnick-Fraser syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change creates a premature translational stop signal (p.Arg297*) in the EYA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYA1 are known to be pathogenic (PMID: 10464653, 18220287). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with branchiootorenal and/or branchiootic syndrome (PMID: 10991693, 11683347; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.790C>T. ClinVar contains an entry for this variant (Variation ID: 429912). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2018

The R297X nonsense variant in the EYA1 gene has been published (as R265X, R264X, and R297X) in association with branchiootorenal syndrome (Rickard et al., 2000; Orten et al., 2008; Wang et al., 2012). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, the R297X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, the R297X variant is pathogenic. -

Branchiootic syndrome 1;C3714941:Otofaciocervical syndrome 1;C4551702:Branchiootorenal syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.86
GERP RS		5.7

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: rs1131691667; hg19: chr8-72184070;