ClinVar Miner

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

dbSNP: rs912928648
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001387301 SCV001587895 pathogenic Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E 2022-02-02 criteria provided, single submitter clinical testing 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%). 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).
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 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.
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

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