NM_001367624.2(ZNF469):c.5548C>A (p.Pro1850Thr) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 1, 2023
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:: RCV000513538.29

Allele description [Variation Report for NM_001367624.2(ZNF469):c.5548C>A (p.Pro1850Thr)]

NM_001367624.2(ZNF469):c.5548C>A (p.Pro1850Thr)

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.5548C>A (p.Pro1850Thr)

Other names:

NM_001127464.1:c.5464C>A; NM_001127464.2:c.5464C>A

HGVS:

NC_000016.10:g.88433018C>A
NG_012236.2:g.10548C>A
NM_001367624.2:c.5548C>AMANE SELECT
NP_001354553.1:p.Pro1850Thr
NC_000016.9:g.88499426C>A

Protein change:

P1850T

Links:

dbSNP: rs199932922

NCBI 1000 Genomes Browser:

rs199932922

Molecular consequence:

NM_001367624.2:c.5548C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000608783	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Nov 1, 2023)	germline	clinical testing	Citation Link,
SCV001795205	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Nov 13, 2020)	germline	clinical testing	Citation Link,
SCV003257067	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 17, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24895405, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000608783

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely benign
(Nov 1, 2023)

germline

clinical testing

Citation Link,

SCV001795205

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Nov 13, 2020)

germline

clinical testing

Citation Link,

SCV003257067

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 17, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus.

Lechner J, Porter LF, Rice A, Vitart V, Armstrong DJ, Schorderet DF, Munier FL, Wright AF, Inglehearn CF, Black GC, Simpson DA, Manson F, Willoughby CE.

Hum Mol Genet. 2014 Oct 15;23(20):5527-35. doi: 10.1093/hmg/ddu253. Epub 2014 Jun 3.

PubMed [citation]

PMID:: 24895405
PMCID:: PMC4168824

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV000608783.29

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

ZNF469: BP4

#	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		5	not provided	not provided	not provided

From GeneDx, SCV001795205.1

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

Description

This variant is associated with the following publications: (PMID: 29111844, 24895405)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003257067.1

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

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1822 of the ZNF469 protein (p.Pro1822Thr). This variant is present in population databases (rs199932922, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with keratoconus (PMID: 24895405). ClinVar contains an entry for this variant (Variation ID: 320941). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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