Submissions for variant NM_001312909.2(FAM111A):c.1706G>A (p.Arg569His)

dbSNP: rs587777011

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000419087	SCV000516941	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28138333, 32765931, 24970356, 23996431, 24635597, 32996714, 33010201, 33258288, 23684011)
Eurofins Ntd Llc (ga)	RCV000419087	SCV000861682	pathogenic	not provided	2018-06-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000988563	SCV001138329	pathogenic	Osteocraniostenosis	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267015	SCV001445196	likely pathogenic	Inborn genetic diseases	2018-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000419087	SCV001587218	pathogenic	not provided	2024-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 569 of the FAM111A protein (p.Arg569His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Kenny-Caffey syndrome (PMID: 23684011, 23996431, 24635597, 24970356). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 56810). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FAM111A protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV000050209	SCV002573250	pathogenic	Autosomal dominant Kenny-Caffey syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000056810). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000050209	SCV002769489	pathogenic	Autosomal dominant Kenny-Caffey syndrome	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function is an unlikely mechanism. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (16 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed multiple times as de novo in individuals with Kenny-Caffey syndrome or nanophthalmos (ClinVar, DECIPHER, PMID: 32996714; PMID: 23684011). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000050209	SCV000082785	pathogenic	Autosomal dominant Kenny-Caffey syndrome	2014-04-01	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000050209	SCV000244019	uncertain significance	Autosomal dominant Kenny-Caffey syndrome	2013-06-27	no assertion criteria provided	literature only
Clinical Genetics Laboratory, Federal University of Health Sciences of Porto Alegre	RCV000050209	SCV000996315	pathogenic	Autosomal dominant Kenny-Caffey syndrome	2014-05-22	no assertion criteria provided	research
Institute of Medical Molecular Genetics, University of Zurich	RCV000050209	SCV001297980	uncertain significance	Autosomal dominant Kenny-Caffey syndrome	2019-08-01	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV001249420	SCV001423422	not provided	Osteocraniostenosis; Autosomal dominant Kenny-Caffey syndrome		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 03-20-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.