Submissions for variant NM_014845.6(FIG4):c.2200G>A (p.Glu734Lys)

gnomAD frequency: 0.00005  dbSNP: rs372846619

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000488398	SCV000279664	uncertain significance	not provided	2015-12-16	criteria provided, single submitter	clinical testing	The E734K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E734K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV001095048	SCV000459637	uncertain significance	Charcot-Marie-Tooth disease type 4J	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000352246	SCV000459638	uncertain significance	Amyotrophic lateral sclerosis type 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000488398	SCV000575491	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000488398	SCV000613296	uncertain significance	not provided	2019-08-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000278522	SCV000946713	uncertain significance	Charcot-Marie-Tooth disease type 4	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 734 of the FIG4 protein (p.Glu734Lys). This variant is present in population databases (rs372846619, gnomAD 0.01%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and/or amyotrophic lateral sclerosis (PMID: 32376792, 35896380). ClinVar contains an entry for this variant (Variation ID: 234661). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000488398	SCV001714180	uncertain significance	not provided	2020-04-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237760	SCV005886631	uncertain significance	not specified	2025-02-04	criteria provided, single submitter	clinical testing	Variant summary: FIG4 c.2200G>A (p.Glu734Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249862 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FIG4 causing Charcot-Marie-Tooth disease type 4J (6.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.2200G>A has been reported in the literature in individuals affected with Charcot-Marie-Tooth disease or Amyotrophic lateral sclerosis without reported genotype/second variant (e.g. Grassano_2022, Kenna_2013, Volodarsky_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie-Tooth disease type 4J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35896380, 23881933, 32376792). ClinVar contains an entry for this variant (Variation ID: 234661). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004742341	SCV005352820	uncertain significance	FIG4-related disorder	2024-08-15	no assertion criteria provided	clinical testing	The FIG4 c.2200G>A variant is predicted to result in the amino acid substitution p.Glu734Lys. This variant has been reported in an individual with Charcot-Marie-Tooth disease (Table S2, Volodarsky et al. 2021. PubMed ID: 32376792) and in two individuals with early-onset Alzheimer's disease (Bartoletti-Stella et al. 2022. PubMed ID: 36133075; eTable 1, Grassano et al. 2022. PubMed ID: 35896380). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.