VCV002685998.1 - ClinVar

NM_002032.3(FTH1):c.487_490dup (p.Ser164Ter)

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002032.3(FTH1):c.487_490dup (p.Ser164Ter)

Variation ID: 2685998 Accession: VCV002685998.1

Type and length

Duplication, 4 bp

Location

Cytogenetic: 11q12.3 11: 61964788-61964789 (GRCh38) [ NCBI UCSC ] 11: 61732260-61732261 (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	Jan 26, 2024	Jan 26, 2024	Jan 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002032.3:c.487_490dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002023.2:p.Ser164Ter	nonsense
NM_001139443.2:c.1640_1643dup		3 prime UTR
NM_001363591.2:c.1640_1643dup		3 prime UTR
NM_001363593.2:c.1640_1643dup		3 prime UTR
NM_004183.2:c.667_670dup
NC_000011.10:g.61964789_61964792dup
NC_000011.9:g.61732261_61732264dup
NG_008346.1:g.7869_7872dup
NG_009033.1:g.19906_19909dup

... more HGVS ... less HGVS

Protein change

S164*

Other names

Canonical SPDI

NC_000011.10:61964788:ATTC:ATTCATTC

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

OMIM: 134770.0002 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.
BEST1		-	-	GRCh38 GRCh37	831	903
FTH1		-	-	GRCh38 GRCh37	-	91

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.
Neurodegeneration with brain iron accumulation 9	Pathogenic (1)	no assertion criteria provided	Jan 10, 2024	RCV003482890.1

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 10, 2024)	no assertion criteria provided Method: literature only	NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV004231698.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (1) PubMed: 37660254 Comment on evidence: In a 13-year-old girl of Indian descent (P1) with neurodegeneration with brain iron accumulation-9 (NBIA9; 620669), Shieh et al. (2023) identified a de novo heterozygous … (more) In a 13-year-old girl of Indian descent (P1) with neurodegeneration with brain iron accumulation-9 (NBIA9; 620669), Shieh et al. (2023) identified a de novo heterozygous 4-bp duplication (c.487_490dupGAAT, NM_002032) in the last exon (exon 4) of the FTH1 gene, resulting in premature termination (ser164 to ter, S164X) in the C terminus, deleting the E-helix region. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Patient fibroblasts showed mildly decreased FTH1 mRNA compared to controls, although mutant-specific transcripts were detectable, indicating escape from nonsense-mediated mRNA decay. Patient fibroblasts showed increased protein levels of both FTH1 and FTL (134790) compared to controls. Patient fibroblasts showed increased iron accumulation compared to controls at 7 days after iron exposure; patient cells also showed increased levels of oxidized proteins and peroxidized lipids, suggesting that the mutation resulted in increased susceptibility to oxidative stress. Molecular modeling predicted that the mutation would disrupt the ferritin E-helix, alter the pore region that is important for iron retention, and thus likely diminish iron-storage capacity. The findings were consistent with a dominant-negative effect. Targeted knockdown of the mutant FTH1 transcript using antisense oligonucleotides (ASOs) in vitro partially rescued the abnormal cellular phenotype. The patient also carried a heterozygous missense variant of uncertain significance (R253W) in the TOE1 gene (613931) that was inherited from the unaffected father. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy.	Shieh JT	HGG advances	2023	PMID: 37660254

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_002032.3(FTH1):c.487_490dup (p.Ser164Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...