NM_022489.4(INF2):c.653G>A (p.Arg218Gln) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003352745.2

Allele description [Variation Report for NM_022489.4(INF2):c.653G>A (p.Arg218Gln)]

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

Gene:

INF2:inverted formin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.33

Genomic location:

Preferred name:

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

HGVS:

NC_000014.9:g.104703440G>A
NG_027684.1:g.18835G>A
NM_001031714.4:c.653G>A
NM_022489.4:c.653G>AMANE SELECT
NM_032714.3:c.653G>A
NP_001026884.3:p.Arg218Gln
NP_071934.3:p.Arg218Gln
NP_116103.1:p.Arg218Gln
NC_000014.8:g.105169777G>A
NM_022489.3:c.653G>A
Q27J81:p.Arg218Gln

Protein change:

R218Q; ARG218GLN

Links:

UniProtKB: Q27J81#VAR_063081; OMIM: 610982.0002; dbSNP: rs267607183

NCBI 1000 Genomes Browser:

rs267607183

Molecular consequence:

NM_001031714.4:c.653G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_022489.4:c.653G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032714.3:c.653G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004076092	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 20023659, 25165188, 29869118, 30126379, 30773290, 30962575, 32901917, 33443052, 33712733, 36506246 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004076092

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Aug 10, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis.

Brown EJ, Schlöndorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, Higgs HN, Henderson JM, Pollak MR.

Nat Genet. 2010 Jan;42(1):72-6. doi: 10.1038/ng.505. Epub 2009 Dec 20. Erratum in: Nat Genet. 2010 Apr;42(4):361. Tonna, Stephen J [added].

PubMed [citation]

PMID:: 20023659
PMCID:: PMC2980844

Novel INF2 mutations in an Italian cohort of patients with focal segmental glomerulosclerosis, renal failure and Charcot-Marie-Tooth neuropathy.

Caridi G, Lugani F, Dagnino M, Gigante M, Iolascon A, Falco M, Graziano C, Benetti E, Dugo M, Del Prete D, Granata A, Borracelli D, Moggia E, Quaglia M, Rinaldi R, Gesualdo L, Ghiggeri GM.

Nephrol Dial Transplant. 2014 Sep;29 Suppl 4:iv80-6. doi: 10.1093/ndt/gfu071.

PubMed [citation]

PMID:: 25165188

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV004076092.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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