Submissions for variant NM_000518.5(HBB):c.45dup (p.Trp16fs)

dbSNP: rs35383398

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780312	SCV000917479	pathogenic	Hemoglobinopathy	2018-05-04	criteria provided, single submitter	clinical testing	Variant summary: HBB c.45dupG (p.Trp16ValfsX8) 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 (e.g., p.Lys18fsX2 and p.Glu27X). The variant allele was found at a frequency of 4.1e-06 in 245968 control chromosomes. c.45dupG has been reported in the literature in multiple individuals affected with Beta Thalassemia and is referred to in the literature as a common Chinese mutation (Chan_1988, Lin_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV003556029	SCV004294110	pathogenic	not provided	2023-06-27	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: 15426). This variant is also known as insertion of G between codon 14/15 or c.45_46insG. This premature translational stop signal has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 2901867, 28671035, 33092414). This variant is present in population databases (rs35383398, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Trp16Valfs*8) 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).
OMIM	RCV000016683	SCV000036953	pathogenic	Beta zero thalassemia	1988-10-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078383	SCV001244581	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078383	SCV002091605	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing