Submissions for variant NM_000518.5(HBB):c.274C>T (p.Leu92=)

gnomAD frequency: 0.00001  dbSNP: rs769583496

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000756242	SCV000601265	uncertain significance	not provided	2024-10-28	criteria provided, single submitter	clinical testing	The HBB c.274C>T (p.Leu92=) synonymous variant (also known as CD 91 CTG>TTG) has been reported to occur in cis with a pathogenic HBB splice variant in individuals with clinical features of beta-thalassemia minor (PMIDs: 8091935 (1994), 12144056 (2002)). The frequency of this variant in the general population, 0.00027 (5/18386 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 predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756242	SCV000883992	uncertain significance	not provided	2018-02-07	criteria provided, single submitter	clinical testing	The HBB c.274C>T; Leu91Leu variant (rs769583496) has been observed in Korean and Japanese individuals harboring a pathogenic allele (Park 2002, Wakamatsu 1994); it is not definitive whether these variants were confirmed to be in cis by molecular analyses, but they are reported as linked variants in the Japanese population. Erythrocyte indices (Hb, HbA2, HbF, MCV, MCH) in four individuals reported by Wakamatsu et al are most consistent with beta-thalassemia minor. This variant is reported in ClinVar (Variation ID: 439144) and is observed in the general population at a low overall frequency of 0.003% (7/246192 alleles, 6 alleles in East Asian population) in the Genome Aggregation Database. This is a synonymous change, the nucleotide is moderately conserved, and computational algorithms (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer, Human Splicing Finder) predict that this variant may impact splicing by strengthening a nearby cryptic donor site. However, given the lack of clinical and functional data, the significance of this variant on its own cannot be determined with certainty. References: Park S et al. Beta-thalassemia in the Korean population. Hemoglobin. 2002 May;26(2):135-45. Wakamatsu C et al. Molecular basis of beta-thalassemia in Japan: heterogeneity and origins of mutations. Acta Haematol. 1994;91(3):136-43.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507587	SCV000919465	likely benign	not specified	2019-08-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756242	SCV001013881	likely benign	not provided	2024-03-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104255	SCV001261105	uncertain significance	Fetal hemoglobin quantitative trait locus 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104256	SCV001261106	uncertain significance	Hemoglobin E	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104257	SCV001261107	uncertain significance	beta Thalassemia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104258	SCV001261108	uncertain significance	Hb SS disease	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV004629226	SCV005128494	likely benign	Inborn genetic diseases	2024-05-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.