Submissions for variant NM_000146.4(FTL):c.-161C>T

dbSNP: rs398124636

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036071	SCV001199418	pathogenic	Hereditary hyperferritinemia with congenital cataracts; Neuroferritinopathy	2023-07-20	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the FTL gene. It does not change the encoded amino acid sequence of the FTL protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FTL function (PMID: 8233801). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 16480). This variant is also known as +39C>U, +39C>T. This variant has been observed in individual(s) with FTL-related conditions (PMID: 9414313, 10366790, 10366804; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Fulgent Genetics, Fulgent Genetics	RCV002482882	SCV002803545	likely pathogenic	Hereditary hyperferritinemia with congenital cataracts; Neuroferritinopathy; L-ferritin deficiency	2021-09-05	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000017944	SCV003922342	likely pathogenic	Hereditary hyperferritinemia with congenital cataracts	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.-161C>T variant in FTL was identified by our study in one individual with hyperferritinemia. The c.-161C>T variant in FTL has been previously reported in three individuals with hereditary hyperferritinemia with congenital cataracts (PMID: 10366790, PMID: 9414313, PMID: 10366804). This variant was found to be de novo in one individual with confirmed paternity and maternity (PMID: 10366804). This variant was absent from large population studies. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 16480) and has been interpreted as pathogenic by Invitae and OMIM. In vitro functional studies provide some evidence that the c.-161C>T variant may impact protein function (PMID: 8233801). However, these types of assays may not accurately represent biological function. Multiple variants in the same region as c.-161C>T variant have been reported in association with disease in the literature and the c.-161C>T variant is located in the iron-responsive element (IRE) domain of FTL, which is involved in regulating L-ferritin expression, suggesting suggesting that this variant is in a hot spot and key functional domain and slightly supports pathogenicity (PMID: 19800271, 7493028, 23421845, 10383191, 22881709, 9226182). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant hereditary hyperferritinemia with congenital cataracts. ACMG/AMP Criteria applied: PS2, PS3_Supporting, PS4_Supporting, PM1_Supporting, PM2_Supporting (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV004597729	SCV005092634	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	FTL: PS2, PM2, PS4:Moderate, PP4, PS3:Supporting
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004597729	SCV005199047	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000017944	SCV000038223	pathogenic	Hereditary hyperferritinemia with congenital cataracts	2013-02-19	no assertion criteria provided	literature only