VCV000000550.14 - ClinVar

NM_000140.5(FECH):c.68-23C>T

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000140.5(FECH):c.68-23C>T

Variation ID: 550 Accession: VCV000000550.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q21.31 18: 57580222 (GRCh38) [ NCBI UCSC ] 18: 55247454 (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 13, 2017	Feb 14, 2024	Jan 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000140.5:c.68-23C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001012515.4:c.68-23C>T		intron variant
NM_001371094.1:c.68-23C>T		intron variant
NM_001371095.1:c.-149-23C>T		intron variant
NM_001374778.1:c.68-23C>T		intron variant
NC_000018.10:g.57580222G>A
NC_000018.9:g.55247454G>A
NG_008175.1:g.11516C>T
LRG_1080:g.11516C>T
LRG_1080t1:c.68-23C>T
LRG_1080t2:c.68-23C>T

... more HGVS ... less HGVS

Protein change

Other names

IVS1, C-T, -23

Canonical SPDI

NC_000018.10:57580221:G:A

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.

0.33466 (A)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.25880

The Genome Aggregation Database (gnomAD) 0.27629

Trans-Omics for Precision Medicine (TOPMed) 0.28790

1000 Genomes Project 30x 0.33385

1000 Genomes Project 0.33466

Links

OMIM: 612386.0003 dbSNP: rs2269219 ClinGen: CA251507 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 1729699 Fig. 5 to determine the location of this allele on the current reference sequence.

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.
FECH		-	-	GRCh38 GRCh37	315	412
LOC130062555	-	-	-	GRCh38	-	31

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.
Protoporphyria, erythropoietic, 1	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Dec 8, 2021	RCV000000580.10
Erythema Jaundice	Likely benign (1)	no assertion criteria provided	Jan 25, 2016	RCV000415389.2
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV001520174.7

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.
Uncertain significance (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Protoporphyria, erythropoietic, 1 Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital Muenster Accession: SCV002496158.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Comment: ACMG categories: PS5,BS2,BP6,BP7 Number of individuals with the variant: 1 Clinical Features: Increased erythrocyte protoporphyrin concentration (present) Age: 10-19 years Sex: female Tissue: blood
Benign (Nov 11, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001950492.2 First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 8280787, 1729699, 27884173, 26789144)
Benign (Jan 24, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001729223.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Protoporphyria, erythropoietic, 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140909.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Protoporphyria, erythropoietic, 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368183.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely benign.
Benign (Aug 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Protoporphyria, erythropoietic, 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001933421.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (Jan 01, 1992)	no assertion criteria provided Method: literature only	PROTOPORPHYRIA, ERYTHROPOIETIC, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020729.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2018	Publications: PubMed (1) PubMed: 1729699 Comment on evidence: In EBV-transformed lymphoblastoid cells from a 12-year-old white girl with cutaneous photosensitivity characteristic of erythropoietic protoporphyria (EPP1; 177000), Nakahashi et al. (1992) found that ferrochelatase … (more) In EBV-transformed lymphoblastoid cells from a 12-year-old white girl with cutaneous photosensitivity characteristic of erythropoietic protoporphyria (EPP1; 177000), Nakahashi et al. (1992) found that ferrochelatase activity, immunochemically quantifiable protein, and mRNA content were about one-half normal. In contrast, the rate of transcription of FECH mRNA in the proband's cells was normal, suggesting that decreased FECH mRNA was due to unstable transcript. cDNA clones encoding ferrochelatase in the proband, isolated by amplification using the polymerase chain reaction (PCR), were found either to encode the normal protein or an abnormal protein that lacked exon 2. Genomic DNA analysis demonstrated that the abnormal allele had a point mutation, C-to-T, near the acceptor site of intron 1. The findings in this patient were thought to confirm autosomal dominant inheritance, at least for this mutation. Both intron 1 and intron 2 of the FECH gene are exceedingly long (8 kb and 7 kb, respectively). (less)
Likely benign (Jan 25, 2016)	no assertion criteria provided Method: clinical testing	Erythema Jaundice Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492646.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017

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
The molecular defect of ferrochelatase in a patient with erythropoietic protoporphyria.	Nakahashi Y	Proceedings of the National Academy of Sciences of the United States of America	1992	PMID: 1729699

Text-mined citations for rs2269219 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000140.5(FECH):c.68-23C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2269219 ...