ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.363A>C (p.Lys121Asn) (rs34726542)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589733 SCV000697125 uncertain significance not provided 2016-09-28 criteria provided, single submitter clinical testing Variant summary: The HBB c.363A>C (p.Lys121Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was not found in 121384 control chromosomes in the ExAC database; however, it was found in 4/552 control chromsomes in the Indian population at a frequency of 0.00725. Although this frequency does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803), all 4 alleles were from two healthy individuals whom were homozygous for the variant of interest, suggesting that it is unlikely to be pathogenic. Although this variant was also found in two individuals who were compound heterozygous for this variant and another BTHAL-0 variant, the subjects had BTHAL MINOR, suggesting the variant is clinically silent (Pinkerton_1979 and Hirsch_1997). The variant has also been found in patients with alpha-thalassemia and iron deficiency, renal calculi, diabetes mellitues and hypertension; the variety of observed phenotypes suggests that the variant is not associated with hemoglobinopathy. Although this variant has been shown to significantly delay crystallization of hemolysate (Hirsch_1997), its functional role in hemoglobinopathy is not clear. OMIM classified this variant as pathogenic, however, this classification has not been updated since 1979 and could be questionable. Taken together, this variant is classified as VUS-possibly benign variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000016568 SCV000883975 benign not specified 2019-01-03 criteria provided, single submitter clinical testing
OMIM RCV000016568 SCV000036837 pathogenic not specified 1979-01-01 no assertion criteria provided literature only

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