ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.251del (p.Gly84fs) (rs193922555)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507807 SCV000601262 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169623 SCV000697101 pathogenic beta Thalassemia 2017-05-24 criteria provided, single submitter clinical testing Variant summary: The HBB c.251delG (p.Gly84Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB 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. c.287dupA, p.Leu97fs). The variant of interest has not been found in a large and broad control population from ExAC in 121390 control chromosomes. This variant was reported in patients with beta thalassemia in a homozygous state as well compound heterozygotes with other pathogenic variants, including evidence of cosegregation with disease (El-Kalla_1997, Rahimi_2010, Al-Allawi_2014, and Ulasli_2015). In an Iraqi study that included 74 beta thalassemia patients, it was found in nine patients and was the third most common mutation (Al-Allawi_2014). In another Iranian study that included 185 beta thalassemia patients, its allele frequency was 1.08% (Rahimi_2010). Available data including clinical and biochemical picture of heterozygous carriers supports that this variant causes transfusion-dependent thalassemia in a homozygous state or in a compound heterozygous state with another severe (beta0) variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000507807 SCV001374567 pathogenic not provided 2019-05-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly84Alafs*6) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with beta thalassemia (PMID: 24719849, 2525253, 28670940, 27756326). This variant is also known as 250delG and 82/83 (-G) in the literature. ClinVar contains an entry for this variant (Variation ID: 36306). Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000169623 SCV000221151 pathogenic beta Thalassemia 2015-11-16 no assertion criteria provided clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000169623 SCV001244555 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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