Ataxia and cerebellar anomalies - narrow panel

Gene: FTH1

Green List (high evidence)

Three monoallelic terminating FTH1 variants (NM_002032: c.487_490 dupGAAT, (p.Ser164*), c.512_513delTT, (p.Phe171*), c.409_410del; p.H137fs*) have been associated with Neurodegeneration with brain iron accumulation 9 (OMIM: 620669)(PMID:37660254; 37265023) in six unrelated cases. Shieh et al (PMID:37660254), report patient fibroblasts studies, which indicate that variants c.487_490 dupGAAT and c.512_513delTT escape nonsense-mediated mRNA decay, resulting in a C-terminally truncated protein, which is predicted to have a dominant-negative effect. Molecular modeling predicts that this could reduce the iron-storage capacity, resulting in iron accumulation. Shieh et al go onto demonstrate that the targeted knockdown of the S164* FTH1 transcript, with antisense oligonucleotides in vitro partially rescued the abnormal cellular phenotype.

Created: 16 Dec 2024, 6:41 p.m. | Last Modified: 16 Dec 2024, 6:41 p.m.

Panel Version: 2.11

Phenotypes
Neurodegeneration with brain iron accumulation 9, OMIM:620669

Publications

• 37660254
• 37265023

The rating of this gene has been updated from Amber to Red following NHS Genomic Medicine Service approval.

Created: 29 Jul 2022, 1:47 p.m. | Last Modified: 29 Jul 2022, 1:47 p.m.

Panel Version: 1.35

Red List (low evidence)

Single family reported in 2001, no reports since that I can identify. Note 5'UTR variant.

Created: 22 Jan 2021, 7:43 a.m. | Last Modified: 22 Jan 2021, 7:43 a.m.

Panel Version: 1.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hemochromatosis, type 5, MIM# 615517

Publications

• 11389486

I don't know

Green List (high evidence)

Gene rating submitted by Steve Keeney Molecular Diagnostics Centre Central Manchester NHS Foundation Trust January 2019 on behalf of North West GLH for the GMS Haematology specialist test group.

Created: 18 Feb 2019, 11:45 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
615517 HEMOCHROMATOSIS, TYPE 5; HFE5

Green List (high evidence)

Gene rating submitted by Mandy Nesbitt Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Trust January 2019 on behalf of Yorkshire and North East GLH for the GMS Haematology specialist test group.

Created: 13 Feb 2019, 12:36 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
615517 HEMOCHROMATOSIS, TYPE 5; HFE5

Red List (low evidence)

Gene rating submitted by Frances Smith Viapath Kings College Hospital February 2019 on behalf of London South GLH for the GMS Haematology specialist test group.

Created: 8 Feb 2019, 5:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
615517 ?Hemochromatosis, type 5

Publications

• 11389486

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Comment on list classification: Downgraded from Green to Amber. As discussed with the GMS Haematology Specialist Test Group at workshop 2nd July 2019. All agreed that there is only enough evidence to rate this gene to Amber.

Created: 22 Jul 2019, 3:05 p.m. | Last Modified: 22 Jul 2019, 3:09 p.m.

Panel Version: 0.44

Discrepant reviews, to be discussed at July workshop to agree rating.

Created: 22 Jul 2019, 3:04 p.m. | Last Modified: 22 Jul 2019, 3:04 p.m.

Panel Version: 0.42

Follow up email correspondence with Patricia Bignell 13th March (webex 8.03.19 WWMGLH comments v1.doc), on behalf of Wessex and the West Midlands GLH for the GMS Haematology specialist test group, suggested rating Amber

Created: 28 May 2019, 2:08 p.m.

Initial gene list (Consensus Genes for SPEC HAEM Panels 31.01.19 North West v1 FINAL.xlsx) collated by Steve Keeney Molecular Diagnostics Centre Central Manchester NHS Foundation Trust January 2019 on behalf of North West GLH for the GMS Haematology specialist test group. Gene Symbol submitted: FTH1; Suggested initial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Phenotypes: 615517 HEMOCHROMATOSIS, TYPE 5; HFE5; PMID(s): none submitted

Created: 18 Feb 2019, 11:49 a.m.

Initial gene list (Consensus Genes for Panels_Haem_SHEFFIELD-29.01.2019.xlsx) collated by Mandy Nesbitt Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Trust January 2019 on behalf of Yorkshire and North East GLH for the GMS Haematology specialist test group. Gene Symbol submitted: FTH1; Suggested intial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Phenotypes: 615517 HEMOCHROMATOSIS, TYPE 5; HFE5; PMID(s): none submitted

Created: 13 Feb 2019, 12:39 p.m.

Initial gene list (Consensus Genes for Haem Panels 17.12.18_KCH.xlsx) collated by Frances Smith Viapath Kings College Hospital February 2019 on behalf of London South GLH for the GMS Haematology specialist test group. Gene Symbol submitted: FTH1; Suggested intial gene rating: Red List (low evidence); Are variants in this gene part of your current diagnostic practice? Yes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Phenotypes: 615517 ?Hemochromatosis, type 5; PMID(s): 11389486

Created: 8 Feb 2019, 5:25 p.m.

Initial gene list (Consensus Genes for Panels 17.12.18_Haem_WWMGLH_v3.xlxs) collated by Carl Fratter Oxford Medical Genetics Laboratories January 2019 on behalf of Wessex and the West Midlands GLH for the GMS Haematology specialist test group. Gene Symbol submitted: FTH1; Suggested initial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? Yes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Phenotypes: 615517 HEMOCHROMATOSIS, TYPE 5; HFE5; PMID(s): 11389486

Created: 5 Feb 2019, 5:51 p.m.

Green List (high evidence)

Gene rating submitted by Carl Fratter Oxford Medical Genetics Laboratories January 2019 on behalf of Wessex and the West Midlands GLH for the GMS Haematology specialist test group.

Created: 5 Feb 2019, 5:50 p.m.

Variants in this GENE are reported as part of current diagnostic practice