Submissions for variant NM_000518.5(HBB):c.235del (p.Leu79fs)

dbSNP: rs281865475

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004561797	SCV000917481	pathogenic	beta Thalassemia	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: HBB c.235delC (p.Leu79TrpfsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251428 control chromosomes (gnomAD). The c.235delC has been reported in the literature in four family members who all had hematological parameters suggestive of being a carriers of b-thal variant (Perea_2004). This report supports the association of the variant with Beta Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 15481896). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001032	SCV001158144	likely pathogenic	not specified	2019-01-17	criteria provided, single submitter	clinical testing	The Cd77/78 (-C) variant (HBB c.235delC; p.Leu79fs variant, also known as Leu78fs when numbered from the mature protein, rs281865475) is reported in the literature in the heterozygous state in individuals affected with beta-thalassemia minor (see link to HbVar and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar for Cd77/78 (-C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2533&.cgifields=histD
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477786	SCV002046749	pathogenic	not provided	2021-01-14	criteria provided, single submitter	clinical testing	The c.235del (p.Leu79Trpfs*11) pathogenic variant is a frameshift mutation that causes the premature termination of beta globin protein synthesis, and has been found among individuals with beta-thalassemia hematological features when in heterozygosity (PMID: 15481896 (2004)).
GeneDx	RCV002477786	SCV005201872	likely pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Reported in the published literature in a family with beta-thalassemia (Perea et al., 2004); Frameshift variant predicted to result in protein truncation, as the last 69 amino acids are replaced with 10 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15481896, 35665479)
OMIM	RCV002280785	SCV000036591	pathogenic	Beta-plus-thalassemia	2004-08-01	no assertion criteria provided	literature only