Submissions for variant NM_000518.5(HBB):c.90C>T (p.Gly30=)

dbSNP: rs35578002

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588766	SCV000697153	pathogenic	beta Thalassemia	2016-12-07	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.90C>T (p.Gly30Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict that this varaint may create a novel 5' splicing donor site and a frameshift change. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121334 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). However, this variant has been reported as a mild beta+ type mutation in numerous patients with beta thalassemia intermedia in homozygous and compound heterozygous states. Ithanet lists variant as a globin gene causative mutation. Taken together, this variant is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269729	SCV001449944	likely pathogenic	not provided	2019-01-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001269729	SCV003834203	likely pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001269729	SCV004219897	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	The HBB c.90C>T (p.Gly30=) synonymous variant has been reported in the published literature in individuals affected with beta(+) thalassemia (PMID: 7786794 (1995), 3828533 (1987)). Additionally, this variant might affect splicing and this might cause the observed beta(+) phenotype in one study (PMID: 3828533 (1987)), and low expression levels of hemoglobin in another study (PMID: 7786794 (1995)). The frequency of this variant in the general population, 0.000004 (1/251342 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on HBB mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000588766	SCV001244430	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000588766	SCV002029166	pathogenic	beta Thalassemia	2021-10-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000588766	SCV002091592	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing