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NM_000140.5(FECH):c.315-48T>C AND not provided

Germline classification:
Pathogenic/Pathogenic, low penetrance (4 submissions)
Last evaluated:
Jan 31, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001381522.21

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:
1

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001579958Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic, low penetrance
(Jan 31, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001950493GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Oct 5, 2023)
germlineclinical testing

Citation Link,

SCV002563477CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(Jan 1, 2021)
germlineclinical testing

Citation Link,

SCV003853551Mayo Clinic Laboratories, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 13, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria.

Gouya L, Martin-Schmitt C, Robreau AM, Austerlitz F, Da Silva V, Brun P, Simonin S, Lyoumi S, Grandchamp B, Beaumont C, Puy H, Deybach JC.

Am J Hum Genet. 2006 Jan;78(1):2-14. Epub 2005 Nov 15.

PubMed [citation]
PMID:
16385445
PMCID:
PMC1380220

Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria.

Balwani M, Doheny D, Bishop DF, Nazarenko I, Yasuda M, Dailey HA, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Liu L, Desnick RJ; Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network..

Mol Med. 2013 Apr 30;19:26-35. doi: 10.2119/molmed.2012.00340.

PubMed [citation]
PMID:
23364466
PMCID:
PMC3646094
See all PubMed Citations (10)

Details of each submission

From Invitae, SCV001579958.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change falls in intron 3 of the FECH gene. It does not directly change the encoded amino acid sequence of the FECH protein. This variant is present in population databases (rs2272783, gnomAD 35%), including at least one homozygous and/or hemizygous individual. This mild variant has been observed in combination with another severe FECH variant in over 90% of individuals with congenital erythropoietic porphyria (PMID: 16385445, 23364466). The vast majority of individuals that are homozygous for this variant do not have clinical symptoms, even in the presence of mild biochemical abnormalities (PMID: 11753383, 29941360). However, a few individuals with milder symptoms have been reported (PMID: 1729699, 16958804, 18758989, 26280465). ClinVar contains an entry for this variant (Variation ID: 562). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the FECH gene, it has been classified as Pathogenic (low penetrance).

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

From GeneDx, SCV001950493.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Observed in the apparent homozygous state in multiple individuals with an erythropoietic protoporphyria phenotype that was reported as either mild or typical and slightly increased erythrocyte-free protoporphyrin concentration or decreased FECH expression (Mizawa et al., 2016; Brancaleoni et al., 2018), but also observed in the apparent homozygous state in a few unaffected individuals from these two studies as well as in numerous individuals in large population cohorts (gnomAD); Published functional studies demonstrate abberant splicing and a mild reduction in enzyme activity (Gouya et al., 2002; Barmin-Aksozen et al., 2017); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 34758253, 21132468, 22591014, 29854403, 30712775, 32313951, 28054335, 28026050, 28093505, 31304091, 23364466, 12601550, 16385445, 18758989, 26280465, 16958804, 29941360, 11753383)

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

From CeGaT Center for Human Genetics Tuebingen, SCV002563477.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV003853551.1

#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 7, 2024