Submissions for variant NM_003227.4(TFR2):c.1127C>A (p.Ala376Asp)

gnomAD frequency: 0.00384  dbSNP: rs41303495

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082557	SCV000633737	likely benign	Hereditary hemochromatosis	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000534616	SCV001155173	likely benign	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164900	SCV001327060	uncertain significance	Hemochromatosis type 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Natera, Inc.	RCV001164900	SCV001459853	benign	Hemochromatosis type 3	2020-01-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000534616	SCV001551493	likely benign	not provided		no assertion criteria provided	clinical testing	The TFR2 p.A205D variant was not identified in the literature nor was it identified in Cosmic and LOVD 3.0. The variant was identified in dbSNP (ID: rs41303495) and in ClinVar (classified as likely benign by Invitae for associated condition of Hereditary Hemochromatosis). The variant was identified in control databases in 683 of 252548 chromosomes (3 homozygous) at a frequency of 0.002704 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 487 of 115588 chromosomes (freq: 0.004213), Other in 21 of 6406 chromosomes (freq: 0.003278), Latino in 76 of 30012 chromosomes (freq: 0.002532), South Asian in 46 of 27714 chromosomes (freq: 0.00166), European (Finnish) in 35 of 23298 chromosomes (freq: 0.001502), African in 17 of 22612 chromosomes (freq: 0.000752) and Ashkenazi Jewish in 1 of 8620 chromosomes (freq: 0.000116), but was not observed in the East Asian population. The p.Ala205 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000534616	SCV001741657	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000534616	SCV001951742	uncertain significance	not provided		no assertion criteria provided	clinical testing