Submissions for variant NM_000518.5(HBB):c.2T>C (p.Met1Thr)

dbSNP: rs33941849

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000029976	SCV000220671	likely pathogenic	beta Thalassemia	2014-09-04	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508042	SCV000601268	pathogenic	not provided	2022-07-20	criteria provided, single submitter	clinical testing	The HBB c.2T>C (p.Met1Thr) variant (also known as Initiation Codon T>C) disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is associated with beta-zero thalassemia (PMIDs: 25849334 (2015), 25806420 (2015), 12368169 (2002), 9101288 (1997)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508042	SCV000603923	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	The HBB c.2T>C; p.Met1? variant (also known as Initiation codon ATG>ACG; rs33941849, HbVar ID: 776) is reported in the literature in individuals affected with beta-thalassemia or beta-thalassemia trait (Jankovic 1990, Molchanova 1998, Muniz 2000, Najmabadi 2002, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical translation initiation codon and is predicted to result in an aberrant or absent protein. Taken together, this variant is considered pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Jankovic L et al. An initiation codon mutation as a cause of a beta-thalassemia. Hemoglobin. 1990;14(2):169-76. PMID: 2272840. Molchanova TP et al. Historical note: the beta-thalassemia allele in the noble Russian family Lermontov is identified as the ATG-->ACG change in the initiation codon. Hemoglobin. 1998;22(3):283-286. PMID: 9629504. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000;64(1):7-14. PMID: 10815781. Najmabadi H et al. Rare and unexpected mutations among Iranian beta-thalassemia patients and prenatal samples discovered by reverse-hybridization and DNA sequencing. Haematologica. 2002;87(10):1113-1114. PMID: 12368169.
Invitae	RCV000508042	SCV002120413	pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing	Disruption of the initiator codon has been observed in individual(s) with HBB-related conditions (PMID: 2272840, 9163586, 25849334, 29379553). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 36310). This variant is also known as CD1 (ATG-ACG). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56.
Genetics and Molecular Pathology, SA Pathology	RCV002465492	SCV002556883	pathogenic	Beta-thalassemia HBB/LCRB	2020-12-18	criteria provided, single submitter	clinical testing
OMIM	RCV000016692	SCV000036962	pathogenic	Beta zero thalassemia	1998-05-01	no assertion criteria provided	literature only
OMIM	RCV000016693	SCV000036963	pathogenic	Beta-thalassemia, lermontov type	1998-05-01	no assertion criteria provided	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029976	SCV000052631	pathogenic	beta Thalassemia	2015-04-21	no assertion criteria provided	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029976	SCV001244630	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000029976	SCV002091623	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing