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

gnomAD frequency: 0.06200  dbSNP: rs2272783

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000000592	SCV000889972	pathogenic	Protoporphyria, erythropoietic, 1	2017-08-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000000592	SCV001140907	likely pathogenic	Protoporphyria, erythropoietic, 1	2019-05-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195427	SCV001365780	pathogenic	Autosomal erythropoietic protoporphyria	2023-10-04	criteria provided, single submitter	clinical testing	The c.333-48T>C variant in FECH is a well-established pathogenic variant for erythropoietic protoporphyria (EPP; Gouya 2002 PMID: 11753383, Gouya 2006 PMID: 16385445, ClinVar Variation ID 562). This variant is found in >95% of individuals with FECH-associated EPP but has also been identified in 6.7% (10341/152102) of pan-ethnic chromosomes in gnomAD, including 817 homozygous individuals (http://gnomad.broadinstitute.org, v3.1.2). In vitro and in vivo functional studies demonstrate that the variant leads to aberrant splicing resulting in a mild but significant reduction in enzyme activity levels (Gouya 2002 PMID: 11753383, Barman-Aksözen 2017 PMID: 28093505). The majority of individuals with FECH-associated EPP carry this hypomorphic c.333-48T>C variant in compound heterozygosity with a rare loss-of-function allele, resulting in enzyme activity levels that are reduced by >70%. Most individuals who are homozygous for the c.333-48T>C variant do not exhibit any clinical symptoms despite having mild biochemical abnormalities; however, a few individuals with milder symptoms such as erythema on the face and extremities, mild photosensitivity after sun exposure have been reported (Mizawa 2016 PMID: 26280465, Alagappan 2017 PMID: 28054335), suggesting that the penetrance and disease severity associated with this variant is determined by the type of variant observed on the second copy of the FECH gene (in trans). In summary, despite its frequency in the general population, this variant is a hypomorphic allele that meets criteria to be classified as pathogenic for autosomal recessive EPP and is expected to cause more severe disease when in compound heterozygosity with a loss-of-function allele. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381522	SCV001579958	pathogenic, low penetrance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV001381522	SCV001950493	pathogenic	not provided	2024-05-26	criteria provided, single submitter	clinical testing	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, 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) (PMID: 26280465, 29941360); In silico analysis indicates 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, 18758989, 16958804, 29941360, 11753383, 16385445, 26280465)
Institute of Human Genetics, University Hospital Muenster	RCV000000592	SCV002496157	likely pathogenic	Protoporphyria, erythropoietic, 1	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PM3,PP6,BS2
Genetics and Molecular Pathology, SA Pathology	RCV000000592	SCV002556470	pathogenic	Protoporphyria, erythropoietic, 1	2020-01-22	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV001381522	SCV002563477	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000000592	SCV002579902	pathogenic	Protoporphyria, erythropoietic, 1	2022-05-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000592	SCV002767242	pathogenic	Protoporphyria, erythropoietic, 1	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with erythropoietic protoporphyria 1 (MIM#177000). (I) 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). (I) 0112 - Heterozygous variants in this gene have been reported to have reduced penetrance (OMIM). (I) 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 splicing leading to a frameshift p.(Asn105Lysfs*8) that is predicted to result in nonsense-mediated decay (NMD) (PMID: 16385445; PMID: 16958804). (SP) 0251 - Variant is heterozygous. (I) 0307 - Variant is present in gnomAD >=0.05 (23726 heterozygotes, 3957 homozygotes). (SB) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 20105171). (SP) 0801 - This variant has 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). (SP) 1001 - This variant has 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). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV001381522	SCV003853551	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000592	SCV004020467	pathogenic	Protoporphyria, erythropoietic, 1	2023-06-01	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000000592	SCV004041112	pathogenic	Protoporphyria, erythropoietic, 1	2023-05-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000000592	SCV004235806	pathogenic	Protoporphyria, erythropoietic, 1	2023-09-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000000592	SCV004806115	uncertain significance	Protoporphyria, erythropoietic, 1	2024-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000000592	SCV000020741	pathogenic	Protoporphyria, erythropoietic, 1	2007-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000000592	SCV000054467	not provided	Protoporphyria, erythropoietic, 1		no assertion provided	literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414979	SCV000492647	uncertain significance	Jaundice; Erythema	2016-01-25	flagged submission	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000592	SCV001368184	uncertain significance	Protoporphyria, erythropoietic, 1	2016-01-01	flagged submission	clinical testing	This variant was classified as: Uncertain significance.
Genomics England Pilot Project, Genomics England	RCV000000592	SCV001760431	likely pathogenic	Protoporphyria, erythropoietic, 1		no assertion criteria provided	clinical testing