ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.217dup (p.Ser73fs) (rs33969853)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507557 SCV000601259 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000576855 SCV000697094 pathogenic beta Thalassemia 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The HBB c.217dupA (p.Ser73Lysfs) 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. p.Gly84fs). One in silico tool predicts a damaging outcome for this variant. Additionally, Cheng_PNAS_1984 reported the absence of beta-globin RNA in erythroid cells of a patient homozygous for this variant. The variant was reported in multiple unrelated BTHAL patients in the literature, and authors all classified the variant as pathogenic. This variant was found in 1/121394 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). Taken together, this variant is classified as pathogenic.
Myriad Women's Health, Inc. RCV000576855 SCV001193879 likely pathogenic beta Thalassemia 2019-12-20 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that S73Kfs*2 is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 6585831. Classification of NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is observed in an individual with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000507557 SCV001410459 pathogenic not provided 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser73Lysfs*2) in the HBB gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to be homozygous in an individual affected with autosomal recessive beta thalassemia (PMID: 6585831). ClinVar contains an entry for this variant (Variation ID: 15419). This variant is also known as c.216_217insA or as an insertion of an A nucleotide between codons 71 and 72 in the literature. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016675 SCV000036945 pathogenic beta^0^ Thalassemia 1984-05-01 no assertion criteria provided literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000576855 SCV001244479 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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