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NM_000140.5(FECH):c.315-48T>C AND Protoporphyria, erythropoietic, 1

Germline classification:
Conflicting interpretations of pathogenicity (14 submissions)
Last evaluated:
Mar 25, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000000592.22

Allele description

NM_000140.5(FECH):c.315-48T>C

Gene:
FECH:ferrochelatase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q21.31
Genomic location:
Preferred name:
NM_000140.5(FECH):c.315-48T>C
HGVS:
  • NC_000018.10:g.57571588A>G
  • NG_008175.1:g.20150T>C
  • NM_000140.5:c.315-48T>CMANE SELECT
  • NM_001012515.4:c.333-48T>C
  • NM_001371094.1:c.315-48T>C
  • NM_001371095.1:c.99-48T>C
  • NM_001374778.1:c.315-48T>C
  • LRG_1080t1:c.315-48T>C
  • LRG_1080t2:c.333-48T>C
  • LRG_1080:g.20150T>C
  • NC_000018.9:g.55238820A>G
  • NM_000140.3:c.315-48T>C
  • NM_000140.4:c.315-48T>C
  • NM_001012515.2:c.333-48T>C
Nucleotide change:
IVS3AS, T-C, -48
Links:
OMIM: 612386.0015; dbSNP: rs2272783
NCBI 1000 Genomes Browser:
rs2272783
Molecular consequence:
  • NM_000140.5:c.315-48T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001012515.4:c.333-48T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001371094.1:c.315-48T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001371095.1:c.99-48T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001374778.1:c.315-48T>C - intron variant - [Sequence Ontology: SO:0001627]
Observations:
3

Condition(s)

Name:
Protoporphyria, erythropoietic, 1 (EPP1)
Synonyms:
Heme synthetase deficiency; Ferrochelatase deficiency; Erythropoietic Protoporphyria, Autosomal Recessive
Identifiers:
MONDO: MONDO:0008319; MedGen: C4692546; Orphanet: 79278; OMIM: 177000

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000020741OMIM
no assertion criteria provided
Pathogenic
(Sep 1, 2007)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV000054467GeneReviews
no classification provided
not providedunknownliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000889972Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 22, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001140907Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2017)
Likely pathogenic
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV001368184Centre for Mendelian Genomics, University Medical Centre Ljubljana
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 1, 2016)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001760431Genomics England Pilot Project, Genomics England
no assertion criteria provided

(ACGS Guidelines, 2016)
Likely pathogenicgermlineclinical testing

Citation Link,

SCV002496157Institute of Human Genetics, University Hospital Muenster
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Dec 8, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002556470Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 22, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002579902MGZ Medical Genetics Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 12, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002767242Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 26, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004020467Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Jun 1, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004041112Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 21, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004235806Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 19, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004806115Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Mar 25, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownnot providednot providednot providednot providednot providednot providedliterature only
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes3not providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease.

Herrero C, To-Figueras J, Badenas C, Méndez M, Serrano P, Enríquez-Salamanca R, Lecha M.

Arch Dermatol. 2007 Sep;143(9):1125-9.

PubMed [citation]
PMID:
17875872

Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias.

Gouya L, Puy H, Robreau AM, Lyoumi S, Lamoril J, Da Silva V, Grandchamp B, Deybach JC.

Hum Genet. 2004 Feb;114(3):256-62. Epub 2003 Dec 11.

PubMed [citation]
PMID:
14669009
See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000020741.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

Erythropoietic protoporphyria-1 (EPP1; 177000) most often results from inheritance of this low-expression mutation (IVS3-48C) in trans with a null FECH allele (Herrero et al., 2007).

Gouya et al. (2002) described an intronic single-nucleotide polymorphism, IVS3-48T-C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism, producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression. Gouya et al. (2002) suggested that this explained the incomplete penetrance of EPP. Using 25 families with EPP caused by identified mutations, they unambiguously determined the haplotypes of 19 independent chromosomes bearing a normal-expression allele and 23 independent chromosomes bearing a low-expression allele in trans to the mutated allele in asymptomatic carrier parents and individuals with overt EPP, respectively. By genotyping of 25 family members with EPP, they showed that, in trans to a specific FECH mutated allele, only the IVS3-48C polymorphism cosegregated with low-expression FECH allele in all individuals with overt EPP. Moreover, the IVS3-48T polymorphism cosegregated with the normal-expression allele in all the asymptomatic carriers. Genotyping of 40 additional unrelated individuals with EPP revealed that 38 had an IVS3-48C allele. Analysis of the intron 3/exon 4 sequence revealed the presence of a cryptic acceptor splice site 63 bp upstream from the one that is normally used. To test the effect of the IVS3-48T-C transition on splicing efficiency, Gouya et al. (2002) subcloned in a eukaryotic expression vector a 1,936-bp genomic fragment spanning exons 3-4 that differed only at the T/C nucleotide. Transfection of the IVS3-48C and IVS3-48T minigenes showed that in both cases the physiologic and the predicted cryptic acceptor sites were used, but with different efficiency. The IVS3-48C minigene gave rise to 40% aberrantly spliced mRNA, and the IVS3-48T minigene to only 20%.

To confirm in a larger cohort that the low expression of a wildtype allelic variant is generally required for EPP to be clinically expressed, Gouya et al. (2004) studied 55 patients and a control group of 80 unrelated subjects of Caucasian origin. They confirmed that the wildtype low-expressed allele phenomenon is usually operative in a mechanism suggesting incomplete penetrance in EPP.

Gouya et al. (2006) showed that the frequency of the IVS3-48C allele differed from 43% in Japanese to less than 1% in black West Africans. They concluded that the mutation may have occurred not long after the Diaspora out of Africa.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000054467.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV000889972.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Mendelics, SCV001140907.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368184.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was classified as: Uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Genomics England Pilot Project, Genomics England, SCV001760431.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, University Hospital Muenster, SCV002496157.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

ACMG categories: PM3,PP6,BS2

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providedbloodnot provided1not providednot providednot provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556470.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

In summary, despite its frequency in the general population, this variant meets criteria to be classified as pathogenic for autosomal recessive EPP; however, it should be noted that this variant is only expected to cause disease when in compound heterozygosity with a loss-of-function allele.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From MGZ Medical Genetics Center, SCV002579902.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767242.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. However, individuals with a single heterozygous FECH variant are reported to also manifest the phenotype (PMID: 20105171). 0112 - Heterozygous variants in this gene have been reported to have reduced penetrance (OMIM). (N) 0210 - Splice site variant (non-canonical) proven to affect splicing of the transcript with a known effect on protein structure (intron 3 of 10). This variant was shown to cause aberrant splice and is predicted to result in nonsense-mediated decay (NMD) (PMID: 16385445; PMID: 16958804). (P) 0251 - Variant is heterozygous. (N) 0307 - Variant is present in gnomAD >=0.05 (23726 heterozygotes, 3957 homozygotes). (B) 0506 – Splicing in silicos tools are inconclusive, nucleotide is poorly conserved. (N) 0701 - Comparable NMD predicted variants have very strong previous evidence for pathogenicity (PMID: 20105171). (P) 0801 – Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as a hypomorphic allele that causes erythropoietic protoporphyria when in trans with a deleterious variant (ClinVar, PMID: 16385445; PMID: 31304091). (P) 1001 - Strong functional evidence supporting abnormal protein function. Studies with both homozygous and heterozygous patients show significantly reduced FECH activity compared to wild-type (PMID: 16385445; PMID: 16958804). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020467.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: FECH c.315-48T>C is located at a position not widely known to affect splicing. Four/four computational tools predict the variant has no significant impact on splicing, while one predicts that the variant strengthens a cryptic 3' acceptor site, located 63 nucleotides upstream from the canonical site. One publication reports experimental evidence confirming that this variant affects mRNA splicing, i.e. strengthening the activity of a cryptic splice site (a constitutive aberrant acceptor splice site), located 63 nucleotides upstream from the canonical site, thus increasing the amount of the aberrant transcripts from ~20% (normal) to ~40% (Gouya_2002). The variant allele was found at a frequency of 0.11 in 281694 control chromosomes, including 3957 homozygotes (gnomAD). In addition, this variant is reported with even higher allele frequencies in certain subpopulations, i.e. in the Latino- and East Asian subpopulations, with a frequency of frequency of 0.34 and 0.33, respectively. The observed variant frequency and the high number of homozygotes suggests that the variant is benign, even when found in homozygous state. However, this variant (c.315-48T>C) has been reported in the literature in over 95% of patients affected with Erythropoietic Protoporphyria (EPP), who were all compound heterozygotes for a pathogenic LoF variant in trans (e.g. Gouya_2002, Colombo_2013, Yasuda_2019). In addition, a mild disease phenotype with incomplete penetrance was also reported for homozygotes (e.g. Mizawa_2016). These data suggest that the pathogenicity (severity and penetrance) of the variant is genotype-dependent, i.e. largely determined by the variant observed in trans. Publications reporting experimental evidence suggest that the abnormally spliced mRNA is degraded by NMD (Gouya_2002), and FECH activity in peripheral blood lymphocytes from individuals who were homozygous for the C-allele was ~38% compared to individuals who were homozygous for the T-allele (Tahara_2010). The following publications have been ascertained in the context of this evaluation (PMID: 22591014, 16385445, 11753383, 26280465, 21132468, 30594473). Thirteen ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely pathogenic, and nine as pathogenic. Based on the evidence outlined above, the variant seems to be a hypomorphic allele that is subject to interallelic interactions which might result in an incomplete penetrance, however it is considered pathogenic, when in found in trans with a LoF variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004041112.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV004235806.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806115.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024