dbSNP rs121909202: EYA1:p.Arg361* (chr8-71244662-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000503.6(EYA1):c.1081C>T(p.Arg361*) variant causes a stop gained change involving the alteration of a non-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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EYA1
NM_000503.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 1.76

Variant links:

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]

EYA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 8-71244662-G-A is Pathogenic according to our data. Variant chr8-71244662-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71244662-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6 link	c.1081C>T	p.Arg361*	stop_gained	Exon 12 of 18	ENST00000340726.8	NP_000494.2	Q99502-1A0A024R813B3KXR1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8 link	c.1081C>T	p.Arg361*	stop_gained	Exon 12 of 18	1	NM_000503.6	ENSP00000342626.3		Q99502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725014

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Branchiootic syndrome 1

Pathogenic:2

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4_MOD,PM2 -

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

EYA1-related disorder

Pathogenic:2

Mar 05, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2 -

Mar 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The EYA1 c.1081C>T variant is predicted to result in premature protein termination (p.Arg361*). This variant is alternatively referred to as c.982C>T in the literature. This variant has been reported in individuals with branchiootorenal syndrome, and in some cases was determined to be de novo (Spruijt et al. 2006. PubMed ID: 16691597; Sloan-Heggen et al. 2016. PubMed ID: 26969326; Orten et al. 2008. PubMed ID: 18220287; Fu et al. 2022. PubMed ID: 36307859). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in EYA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:2

Sep 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18177466, 25525159, 26969326, 34387732, 31581539, 21280147, 16691597) -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Branchiootorenal syndrome 1

Pathogenic:2

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1081C>T;p.(Arg361*) variant creates a premature translational stop signal in EYA1 gene. It is expected to result in an absent or disrupted protein product -PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7943; PMID: 26969326;18177466; 21280147) - PS4. This variant is not present in population databases (rs121909202, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Inborn genetic diseases

Pathogenic:1

Apr 28, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1081C>T (p.R361*) alteration, located in exon 12 (coding exon 10) of the EYA1 gene, consists of a C to T substitution at nucleotide position 1081. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 361. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The EYA1 c.1081C>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple patients with branchio-oto-renal (BOR) syndrome (Krug, 2011; Olavarrieta, 2008; Orten, 2008; Sloan-Heggen, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Melnick-Fraser syndrome

Pathogenic:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg361*) 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 individual(s) with branchio-oto-renal syndrome (PMID: 16691597, 18177466, 21280147, 26969326). In at least one individual the variant was observed to be de novo. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this EYA1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 10,567 individuals referred to our laboratory for EYA1 testing. This variant is also known as Arg328X. ClinVar contains an entry for this variant (Variation ID: 7943). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Mar 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.12

Eigen_PC

Benign

-0.061

FATHMM_MKL

Benign

0.68

Vest4

0.95

GERP RS

-0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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