VCV000016474.24 - ClinVar

NM_000146.4(FTL):c.-160A>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000146.4(FTL):c.-160A>G

Variation ID: 16474 Accession: VCV000016474.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.33 19: 48965348 (GRCh38) [ NCBI UCSC ] 19: 49468605 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 2, 2017	Oct 20, 2024	Jan 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000146.4:c.-160A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		5 prime UTR
NC_000019.10:g.48965348A>G
NC_000019.9:g.49468605A>G
NG_008152.1:g.5040A>G

Protein change

Other names

-160A-G

Canonical SPDI

NC_000019.10:48965347:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA126550 OMIM: 134790.0001 dbSNP: rs398124633 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FTL		No evidence available	No evidence available	GRCh38 GRCh37	169	215

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary hyperferritinemia with congenital cataracts	Pathogenic (1)	no assertion criteria provided	Feb 19, 2013	RCV000017938.29
Hereditary hyperferritinemia with congenital cataracts Neuroferritinopathy	Pathogenic (1)	criteria provided, single submitter	Jan 16, 2024	RCV001061778.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV002274882.17

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuroferritinopathy Hereditary hyperferritinemia with congenital cataracts Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001226534.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 7493028‚ 11703332‚ 14662596‚ 24766965‚ 30401656 Comment: This variant occurs in a non-coding region of the FTL gene. It does not change the encoded amino acid sequence of the FTL protein. This … (more) This variant occurs in a non-coding region of the FTL gene. It does not change the encoded amino acid sequence of the FTL protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hyperferritinemia and cataract syndrome (PMID: 7493028, 11703332, 14662596, 24766965, 30401656). It has also been observed to segregate with disease in related individuals. This variant is also known as A40G. ClinVar contains an entry for this variant (Variation ID: 16474). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FTL function (PMID: 7493028). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002563540.16 First in ClinVar: Aug 23, 2022 Last updated: Oct 20, 2024	Comment: FTL: PP1:Strong, PM2, PP4:Moderate, PS3:Moderate, PS4:Moderate Number of individuals with the variant: 2
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004026978.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (Feb 19, 2013)	no assertion criteria provided Method: literature only	HYPERFERRITINEMIA WITH OR WITHOUT CATARACT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038217.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 02, 2017	Publications: PubMed (4) PubMed: 23421845‚ 7493028‚ 8781450‚ 12199804 Comment on evidence: This mutation, previously designated here as c.-146A-G, is now referred to as c.-160A-G (+40A-G) (Luscieti et al., 2013). Beaumont et al. (1995) demonstrated that affected … (more) This mutation, previously designated here as c.-146A-G, is now referred to as c.-160A-G (+40A-G) (Luscieti et al., 2013). Beaumont et al. (1995) demonstrated that affected members of a 3-generation family with autosomal dominant hyperferritinemia and cataract (HRFTC; 600886) carried a heterozygous A-to-G transition in the iron-responsive element (IRE) of the FTL gene. The authors referred to the variant as 40A-G. Affected members presented with early-onset bilateral cataract. Slit-lamp examination demonstrated deposits of dust-like spots (pulverulent cataract) in all layers of both lens. There were no other clinical manifestations. All affected members had an elevated level of circulating ferritin with no other hematologic or biochemical abnormalities. Genetic hemochromatosis was excluded by liver biopsy which showed no iron overload but a heavy deposit of lipofuscin pigment in hepatocytes thought to be due to the accumulation of L ferritin. Affected members of the family had an A-to-G transition in the highly conserved CAGUGU motif that constitutes the IRE loop and mediates the high-affinity interaction with the iron regulatory protein (100880). They showed that the mutation abolished the finding of IRP in vitro and leads to a high constitutive, poorly regulated L ferritin synthesis in cultured lymphoblastoid cells established from affected patients. Aguilar-Martinez et al. (1996) identified an A-to-G transition at position 146 of the FTL gene in heterozygous state in an 8-year-old boy and his father, both of whom had hyperferritinemia and cataract. The paternal grandfather also suffered from cataract. Both parents were of French origin. The mother had normal ferritin levels and no cataract. Both this and the 147G-C mutation (134790.0002) involved the 5-base sequence (CAGUG) that characterizes the loop structure of the IRE. (This A-to-G mutation appears to be the same as the A-to-G mutation reported by Beaumont et al. (1995) since the IRE contains only 1 adenine residue.) In a large kindred in which 11 members had hyperferritinemia-cataract syndrome, McLeod et al. (2002) identified the same mutation in the conserved CAGUG motif. They referred to the mutation as an A-to-G change at nucleotide 40. (less)

Comment:

This variant occurs in a non-coding region of the FTL gene. It does not change the encoded amino acid sequence of the FTL protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hyperferritinemia and cataract syndrome (PMID: 7493028, 11703332, 14662596, 24766965, 30401656). It has also been observed to segregate with disease in related individuals. This variant is also known as A40G. ClinVar contains an entry for this variant (Variation ID: 16474). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FTL function (PMID: 7493028). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Frequent Mutation in the FTL Gene Causing Hyperferritinemia Cataract Syndrome in Turkish Population Is c.-160A>G.	Balta B	Turkish journal of haematology : official journal of Turkish Society of Haematology	2019	PMID: 30401656
Hereditary hyperferritinaemia cataract syndrome.	Bowes O	Lancet (London, England)	2014	PMID: 24766965
Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome.	Luscieti S	Orphanet journal of rare diseases	2013	PMID: 23421845
Hereditary hyperferritinemia-cataract syndrome: prevalence, lens morphology, spectrum of mutations, and clinical presentations.	Craig JE	Archives of ophthalmology (Chicago, Ill. : 1960)	2003	PMID: 14662596
Mutation spectrum in Australian pedigrees with hereditary hyperferritinaemia-cataract syndrome reveals novel and de novo mutations.	McLeod JL	British journal of haematology	2002	PMID: 12199804
Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia-cataract syndrome.	Girelli D	British journal of haematology	2001	PMID: 11703332
A novel mutation in the iron responsive element of ferritin L-subunit gene as a cause for hereditary hyperferritinemia-cataract syndrome.	Aguilar-Martinez P	Blood	1996	PMID: 8781450
Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract.	Beaumont C	Nature genetics	1995	PMID: 7493028

Text-mined citations for rs398124633 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000146.4(FTL):c.-160A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398124633 ...