Submissions for variant NM_000146.4(FTL):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs139732572

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001857397	SCV002113514	uncertain significance	Hereditary hyperferritinemia with congenital cataracts; Neuroferritinopathy	2022-03-02	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 96689). Disruption of the initiator codon has been observed in individual(s) with L-ferritin deficiency (PMID: 15173247, 30678075). This variant is present in population databases (rs139732572, gnomAD 0.003%). This sequence change affects the initiator methionine of the FTL mRNA. The next in-frame methionine is located at codon 69.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082857	SCV002571980	likely pathogenic	L-ferritin deficiency	2022-08-12	criteria provided, single submitter	clinical testing	Variant summary: FTL c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met69) is located in the encoded protein. An activation of this potential downstream translation initiation site would result in a shortened protein missing the first 68 amino acids from the protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant allele was found at a frequency of 1.2e-05 in 251104 control chromosomes (gnomAD). c.1A>G has been reported in the literature in at least two heterozygous individuals affected with autosomal dominant L-Ferritin Deficiency (e.g. Cremonesi_2004, Cadenas_2019). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000082857	SCV003761421	uncertain significance	L-ferritin deficiency	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Met1Val variant in FTL was identified by our study in one individual with low serum ferritin. The p.Met1Val variant in FTL has been reported in 2 unrelated individuals with autosomal dominant L-ferritin deficiency (PMID: 30678075, PMID: 15173247) and segregated with disease in 2 affective relatives from one family (PMID: 30678075), but has been identified in 0.003% (3/113706) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs139732572). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. This variant has also been reported in ClinVar (Variation ID: 96689) and has been interpreted as pathogenic by OMIM, as likely pathogenic by LabCorp, and as a variant of uncertain significance by Invitae. This variant is located in the first amino acid and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 69 and there are 2 reported pathogenic or likely pathogenic variants in ClinVar upstream of this downstream methionine. It is of note that loss of function of FTL in an autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun et al., 2018 (PMID: 30192042). In summary, the clinical significance of the p.Met1Val variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV003884347	SCV004702207	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FTL: PM2, PS4:Moderate, PVS1:Moderate, PP1, PP4
OMIM	RCV000082857	SCV000114909	pathogenic	L-ferritin deficiency	2004-06-01	no assertion criteria provided	literature only