Submissions for variant NM_022489.4(INF2):c.640C>T (p.Arg214Cys)

dbSNP: rs912928648

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387301	SCV001587895	pathogenic	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2022-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 214 of the INF2 protein (p.Arg214Cys). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt INF2 protein function. ClinVar contains an entry for this variant (Variation ID: 635443). This missense change has been observed in individuals with focal segmental glomerulosclerosis (PMID: 21258034, 25165188, 28780565). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000786896	SCV002768949	pathogenic	Focal segmental glomerulosclerosis 5	2022-02-02	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. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. In some families with focal segmental glomerulosclerosis (FSGS), carriers of pathogenic variants were clinically unaffected (PMID: 32451589). (I) 0115 - Variants in this gene are known to have variable expressivity. Inter- and intrafamilial variability has been reported, where the same variant was observed in individuals with FSGS or both FSGS and Charcot-Marie-Tooth disease (CMT) (PMID: 32451589). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. The diaphanous FH3 domain is a cluster of pathogenic variants (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg214His) has been reported as a recurrent variant in multiple families with FSGS with incomplete penetrance (PMID: 32451589). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple families with FSGS with incomplete penetrance (PMID: 32451589) and has two pathogenic entries in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion, Medical Genetics	RCV000786896	SCV004013795	pathogenic	Focal segmental glomerulosclerosis 5		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000635443 / PMID: 21258034) and a different missense change at the same codon (p.Arg214His / ClinVar ID: VCV000001053 / PMID: 20023659) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813139	SCV005438421	pathogenic	Charcot-Marie-Tooth disease dominant intermediate E	2024-12-18	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786896	SCV000925795	pathogenic	Focal segmental glomerulosclerosis 5	2018-11-09	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000790333	SCV000929743	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only