rs36015961
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000518.5(HBB):c.344T>C(p.Leu115Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L115?) has been classified as Pathogenic.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.344T>C | p.Leu115Pro | missense_variant | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.344T>C | p.Leu115Pro | missense_variant | 3/3 | 1 | NM_000518.5 | P1 | |
HBB | ENST00000647020.1 | c.344T>C | p.Leu115Pro | missense_variant | 3/3 | P1 | |||
HBB | ENST00000475226.1 | n.276T>C | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
HBB | ENST00000633227.1 | c.*160T>C | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 26, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 23, 2021 | - - |
Dominant beta-thalassemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2023 | Variant summary: HBB c.344T>C (p.Leu115Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251222 control chromosomes (gnomAD). c.344T>C (aka. Hb Durham-N.C. or Hb Brescia) has been reported in the literature in multiple individuals affected with Dominant Beta Thalassemia (e.g. Curuk_1994, deCastro_1994, Rund_1997, Park_2002, Ropero_2012), and in many of these cases inclusion body formation was also noted. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8980256, 8111050, 8037185, 12144056, 21845419). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
beta Thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 15, 2017 | - - |
Beta thalassemia intermedia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
HEMOGLOBIN DURHAM-N.C. Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
HEMOGLOBIN BRESCIA Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at