NM_001367624.2(ZNF469):c.2297G>A (p.Arg766Gln) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Dec 17, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000325707.4

Allele description [Variation Report for NM_001367624.2(ZNF469):c.2297G>A (p.Arg766Gln)]

NM_001367624.2(ZNF469):c.2297G>A (p.Arg766Gln)

Gene:

ZNF469:zinc finger protein 469 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.2

Genomic location:

Preferred name:

NM_001367624.2(ZNF469):c.2297G>A (p.Arg766Gln)

Other names:

NM_001127464.1:c.2297G>A; NM_001127464.2:c.2297G>A

HGVS:

NC_000016.10:g.88429767G>A
NG_012236.2:g.7297G>A
NM_001367624.2:c.2297G>AMANE SELECT
NP_001354553.1:p.Arg766Gln
NC_000016.9:g.88496175G>A

Protein change:

R766Q

Links:

dbSNP: rs144492145

NCBI 1000 Genomes Browser:

rs144492145

Molecular consequence:

NM_001367624.2:c.2297G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000491427	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 12, 2016)	germline	clinical testing	Citation Link,
SCV005883328	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Dec 17, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000491427

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 12, 2016)

germline

clinical testing

Citation Link,

SCV005883328

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Dec 17, 2024)

germline

clinical testing

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000491427.1

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

Description

A variant of uncertain significance has been identified in the ZNF469 gene. The R766Q variant has been reported inone European patient with keratoconus and classified as a polymorphism (Lechner et al., 2014). The R766Q variant was not observed in approximately 2,200 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project (average read depth: 5.0), and was not observedwith any significant frequency in the Exome Aggregation Consortium (ExAC). The R766Q variant is asemi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ insome properties. However, this substitution occurs at a position that is not conserved across species, and in silicoanalysis predicts this variant likely does not alter the protein structure/function.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005883328.1

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

Description

Variant summary: ZNF469 c.2297G>A (p.Arg766Gln) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 1544706 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database (v4), including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ZNF469 causing Brittle cornea syndrome 1, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2297G>A in individuals affected with Brittle cornea syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 286776). Based on the evidence outlined above, the variant was classified as likely 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: Apr 28, 2025

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