Submissions for variant NM_022489.4(INF2):c.653G>A (p.Arg218Gln)

dbSNP: rs267607183

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001239762	SCV001412659	pathogenic	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the INF2 protein (p.Arg218Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with focal segmental glomerulosclerosis (FSGS) (PMID: 20023659, 25165188; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1051). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INF2 protein function. Experimental studies have shown that this missense change affects INF2 function (PMID: 20023659, 26764407). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001239762	SCV001752547	pathogenic	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2022-04-08	criteria provided, single submitter	clinical testing
3billion	RCV000001106	SCV002573111	pathogenic	Focal segmental glomerulosclerosis 5	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. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 20023659). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.15). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001051). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 20023659 , 30773290). A different missense change at the same codon (p.Arg218Trp) has been reported to be associated with INF2-related disorder (ClinVar ID: VCV000001052 / PMID: 20023659 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002293970	SCV002587339	pathogenic	Kidney disorder	2022-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003352745	SCV004076092	likely pathogenic	Inborn genetic diseases	2023-08-10	criteria provided, single submitter	clinical testing	The c.653G>A (p.R218Q) alteration is located in exon 4 (coding exon 3) of the INF2 gene. This alteration results from a G to A substitution at nucleotide position 653, causing the arginine (R) at amino acid position 218 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous state in multiple individuals with focal segmental glomerulosclerosis and cosegregates with disease in several families (Morales-Alvarez, 2022; Schrezenmeier, 2021; Seo, 2020; Connaughton, 2019; Bezdíka, 2018; Safarikova, 2018; Caridi, 2014; Brown, 2010). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies collectively show a critical impact of R218Q on the function of INF2 in various model systems and multiple different assays (Sun, 2021; A, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000681691	SCV004226883	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1, PM2_supporting, PS3, PS4_moderate
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001106	SCV005086699	pathogenic	Focal segmental glomerulosclerosis 5	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, both loss of function and gain of function have been suggested (PMID: 32451589). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 32451589). (I) 0115 - Variants in this gene are known to have variable expressivity, with interfamilial and intrafamilial phenotypic variabilities described (PMID: 32451589). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated diaphanous FH3 domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg218Trp) has been classified as pathogenic by two clinical laboratories in Clinvar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar and has been observed in several families with focal segmental glomerulosclerosis in the literature (PMIDs: 20023659, 30773290). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have shown that this variant causes protein mislocalization (PMID: 20023659). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000001106	SCV000021256	pathogenic	Focal segmental glomerulosclerosis 5	2010-01-01	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000681691	SCV000809139	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000001106	SCV000863868	pathogenic	Focal segmental glomerulosclerosis 5	2018-05-17	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000001106	SCV001760330	pathogenic	Focal segmental glomerulosclerosis 5		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV000001106	SCV002106620	pathogenic	Focal segmental glomerulosclerosis 5	2019-02-14	no assertion criteria provided	literature only