Submissions for variant NM_001367624.2(ZNF469):c.3950A>G (p.Lys1317Arg)

gnomAD frequency: 0.00068  dbSNP: rs772817384

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000406466	SCV000399333	uncertain significance	Brittle cornea syndrome 1	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000585365	SCV000534206	uncertain significance	not provided	2025-04-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV000585365	SCV000692876	likely benign	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000585365	SCV002342523	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278454	SCV002565333	uncertain significance	Ehlers-Danlos syndrome	2019-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356433	SCV002622925	likely benign	Cardiovascular phenotype	2022-12-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238899	SCV005887973	likely benign	not specified	2025-01-07	criteria provided, single submitter	clinical testing	Variant summary: ZNF469 c.3950A>G (p.Lys1317Arg) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 1550178 control chromosomes, predominantly at a frequency of 0.004 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Finnish control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ZNF469 causing Brittle cornea syndrome 1 phenotype, suggesting the variant may be benign. To our knowledge, no occurrence of c.3950A>G 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: 320915). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003950091	SCV004761762	likely benign	ZNF469-related disorder	2022-02-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).