Submissions for variant NM_000146.4(FTL):c.169G>A (p.Glu57Lys)

gnomAD frequency: 0.00016  dbSNP: rs201241191

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000395171	SCV000414212	benign	Hereditary hyperferritinemia with congenital cataracts	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000311515	SCV000414213	benign	Neuroferritinopathy	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103735	SCV001001993	likely benign	Hereditary hyperferritinemia with congenital cataracts; Neuroferritinopathy	2025-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000861621	SCV001819176	likely benign	not provided	2019-04-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323416	SCV004030045	uncertain significance	not specified	2023-07-12	criteria provided, single submitter	clinical testing	Variant summary: FTL c.169G>A (p.Glu57Lys) results in a conservative amino acid change located in the Ferritin/DPS protein domain (IPR008331) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251376 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.169G>A in individuals affected with L-Ferritin Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
TilsonLab, Columbia University	RCV000144502	SCV000189821	likely pathogenic	sporadic abdominal aortic aneurysm	2014-09-21	no assertion criteria provided	research	Observed frequency of 48965836(G>A) in 2/19 patients with abdominal aortic aneurysm versus heterozygosity described in "Variation Viewer" as 0.0002.
PreventionGenetics, part of Exact Sciences	RCV004751285	SCV005349935	uncertain significance	FTL-related disorder	2024-07-16	no assertion criteria provided	clinical testing	The FTL c.169G>A variant is predicted to result in the amino acid substitution p.Glu57Lys. This variant has been reported in two individuals with abdominal aortic aneurysm; however, no additional evidence was provided to support pathogenicity (Tilson et al. 2006. PubMed ID: 17182944). In ClinVar, this variant has conflicting interpretations of benign, likely benign, and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/156439/). This variant is reported in 0.41% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is high for a dominant pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.