Submissions for variant NM_001063.4(TF):c.2012G>A (p.Gly671Glu)

gnomAD frequency: 0.00299  dbSNP: rs121918677

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001144085	SCV001304662	likely benign	Atransferrinemia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Mendelics	RCV001144085	SCV002519861	likely benign	Atransferrinemia	2023-12-31	criteria provided, single submitter	clinical testing
Invitae	RCV002513011	SCV003252581	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155024	SCV003844778	likely benign	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: TF c.2012G>A (p.Gly671Glu) results in a non-conservative amino acid change located in the Transferrin-like domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 251236 control chromosomes. The observed variant frequency is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in TF causing Atransferrinemia phenotype (0.0011), strongly suggesting that the variant is benign. c.2012G>A has been reported in the literature, without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Atransferrinemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as likely benign while one classified as pathogneic. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV002513011	SCV004155576	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TF: BS1
PreventionGenetics, part of Exact Sciences	RCV003914834	SCV004733250	likely benign	TF-related condition	2024-01-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000013450	SCV000033697	pathogenic	Transferrin variant B2	1984-05-01	flagged submission	literature only