Submissions for variant NM_014845.6(FIG4):c.205C>T (p.Arg69Cys)

gnomAD frequency: 0.00013  dbSNP: rs540674198

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV003420274	SCV000845393	uncertain significance	FIG4-related disorder	2018-08-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822045	SCV000962826	uncertain significance	Charcot-Marie-Tooth disease type 4	2022-08-06	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 69 of the FIG4 protein (p.Arg69Cys). This variant is present in population databases (rs540674198, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FIG4-related conditions. ClinVar contains an entry for this variant (Variation ID: 587490). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001152672	SCV001313897	uncertain significance	Charcot-Marie-Tooth disease type 4J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001152673	SCV001313898	uncertain significance	Amyotrophic lateral sclerosis type 11	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV001726321	SCV001961993	uncertain significance	not provided	2021-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001726321	SCV001989814	uncertain significance	not provided	2020-04-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002532973	SCV003675822	uncertain significance	Inborn genetic diseases	2022-11-17	criteria provided, single submitter	clinical testing	The c.205C>T (p.R69C) alteration is located in exon 3 (coding exon 3) of the FIG4 gene. This alteration results from a C to T substitution at nucleotide position 205, causing the arginine (R) at amino acid position 69 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003420274	SCV004115950	uncertain significance	FIG4-related disorder	2023-06-07	criteria provided, single submitter	clinical testing	The FIG4 c.205C>T variant is predicted to result in the amino acid substitution p.Arg69Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.018% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-110037687-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.