Submissions for variant NM_000518.5(HBB):c.143_146dup (p.Thr51fs)

dbSNP: rs35619054

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508077	SCV000601248	pathogenic	not provided	2023-03-16	criteria provided, single submitter	clinical testing	The HBB c.143_146dup (p.Thr51Valfs*4) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with beta thalassemia (PMID: 8081396 (1994), 8199027 (1994), 7558874 (1995), 20132300 (2010), 23590658 (2013)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001078409	SCV000919493	pathogenic	beta Thalassemia	2020-10-12	criteria provided, single submitter	clinical testing	Variant summary: HBB c.143_146dupATCT (p.Thr51ValfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251424 control chromosomes (gnomAD). c.143_146dupATCT [also known as CD 47/48 (+ATCT) and as c.146_147insATCT] has been reported in the literature, in the compound heterozygous and homozygous states, in multiple individuals affected with Beta Thalassemia (e.g. Garewal_1994, Jain_1994, Sharma_2010, Hoppe_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000508077	SCV001407287	pathogenic	not provided	2023-01-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 439135). This variant is also known as insertion of 4 nucleotides (ATCT) at codon 48, codons 47/48 (+ATCT). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 8081396). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr51Valfs*4) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309).
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078409	SCV001244614	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation