ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.5T>C (p.Val2Ala) (rs33949930)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756238 SCV000883986 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The Hb Raleigh (HBB: c.5T>C; Val1Ala) variant (rs33949930) has been described in the heterozygous state in asymptomatic individuals with normal hematological parameters (see link to HbVar and references therein). This variant contains an entry in ClinVar (Variation ID: 15323) and is observed in only 1/245880 alleles in the Genome Aggregation Database. The valine at codon 1 is highly conserved and functional studies of this variant protein demonstrate reduced oxygen affinity and dissociation (see link to HbVar and references therein). Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to HbVar:
Integrated Genetics/Laboratory Corporation of America RCV000781459 SCV000919496 uncertain significance not specified 2017-11-29 criteria provided, single submitter clinical testing Variant summary: The HBB c.5T>C (p.Val2Ala) variant, also known as Hb Raleigh, causes a missense change involving the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that Hb Raleigh had a lower oxygen affinity than Hb A throughout the pH range examined but did not affect protein stability (Moo-Penn_1977, Landin_1993). Also, 2,3-diphosphoglycerate and inositol hexaphosphate cofactors addition had less effect on the oxygen affinity of Hb Raleigh than on that of Hb A with chloride ions having the opposite effect. This variant was found in 1/245880 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is widely regarded as clinically silent variant. It was reported in several individuals with no clinical data (Chen_1998, Thongnoppakhun_2009, Canatan_2016,) or normal hematological values in heterozygosity (Landin_2009), including one report where it was occurring in 5 members of the same family where the proband (compound heterozygous with Hb Russ) had normal hematological values (Moo Penn_1977). In addition, an individual who had this variant in compound heterozygous state with HbS showed no specific features of hemoglobinopathy or beta-thalassemia (Sofronescu_2011). Furthermore, an individual, who was a double heterozygote for this variant and alfa gene deletion (c.a-3.7), was generally healthy but had a mild anemia due to the alfa gene deletion (Jain_2011). This structural variant produces spurious HbA1c measurement depending upon methods used, impeding the use of Hb glycosylation as a means to monitor glucose control in diabetic patients with Hb-Raleigh (Chen_1998, Vandewiele_2010, Sofronescu_2011, Singha_2011, Jain_2011). Taken together, this variant is classified as a VUS-possibly benign.
OMIM RCV000016563 SCV000036831 other HEMOGLOBIN RALEIGH 2017-12-12 no assertion criteria provided literature only

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