NM_004100.5(EYA4):c.1223G>A (p.Arg408His) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000216686.5

Allele description [Variation Report for NM_004100.5(EYA4):c.1223G>A (p.Arg408His)]

NM_004100.5(EYA4):c.1223G>A (p.Arg408His)

Genes:

EYA4:EYA transcriptional coactivator and phosphatase 4 [Gene - OMIM - HGNC]
LOC126859796:MED14-independent group 3 enhancer GRCh37_chr6:133826289-133827488 [Gene]
TARID:TCF21 antisense RNA inducing promoter demethylation [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q23.2

Genomic location:

Preferred name:

NM_004100.5(EYA4):c.1223G>A (p.Arg408His)

HGVS:

NC_000006.12:g.133506137G>A
NG_011596.2:g.269781G>A
NM_001301012.2:c.1061G>A
NM_001301013.2:c.1241G>A
NM_001370458.1:c.1154G>A
NM_001370459.1:c.1079G>A
NM_004100.5:c.1223G>AMANE SELECT
NM_172103.4:c.1154G>A
NM_172105.4:c.1223G>A
NP_001287941.1:p.Arg354His
NP_001287942.1:p.Arg414His
NP_001357387.1:p.Arg385His
NP_001357388.1:p.Arg360His
NP_004091.3:p.Arg408His
NP_742101.2:p.Arg385His
NP_742103.1:p.Arg408His
LRG_418t1:c.1223G>A
LRG_418:g.269781G>A
LRG_418p1:p.Arg408His
NC_000006.11:g.133827275G>A
NM_004100.4:c.1223G>A
NR_109982.1:n.2497C>T

Protein change:

R354H

Links:

dbSNP: rs760787542

NCBI 1000 Genomes Browser:

rs760787542

Molecular consequence:

NM_001301012.2:c.1061G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301013.2:c.1241G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370458.1:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370459.1:c.1079G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004100.5:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172103.4:c.1154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172105.4:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_109982.1:n.2497C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271776	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Aug 27, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572081	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 16, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28798025, 33745059 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271776

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Aug 27, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002572081

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 16, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.

Miszalski-Jamka K, Jefferies JL, Mazur W, Głowacki J, Hu J, Lazar M, Gibbs RA, Liczko J, Kłyś J, Venner E, Muzny DM, Rycaj J, Białkowski J, Kluczewska E, Kalarus Z, Jhangiani S, Al-Khalidi H, Kukulski T, Lupski JR, Craigen WJ, Bainbridge MN.

Circ Cardiovasc Genet. 2017 Aug;10(4). doi: 10.1161/CIRCGENETICS.117.001763.

PubMed [citation]

PMID:: 28798025
PMCID:: PMC5665372

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271776.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The p.Arg408His variant in EYA4 has not been previously reported in individuals with hearing loss, but has been identified in 5/66620 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computati onal prediction tools and conservation analysis do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Arg408His variant is uncertain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: EYA4 c.1223G>A (p.Arg408His) results in a non-conservative amino acid change located in the EYA domain (IPR006545) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282562 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYA4 causing Dilated Cardiomyopathy (1.6e-05), suggesting that the variant is benign. c.1223G>A has been reported in the literature in at least one individual affected with Left Ventricular Non-Compaction Cardiomyopathy (Miszalski-Jamka_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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