1-225403394-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP3_StrongPP5
The NM_002296.4(LBR):c.1757G>A(p.Arg586His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R586C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002296.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LBR | NM_002296.4 | c.1757G>A | p.Arg586His | missense_variant | 14/14 | ENST00000272163.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LBR | ENST00000272163.9 | c.1757G>A | p.Arg586His | missense_variant | 14/14 | 1 | NM_002296.4 | P1 | |
LBR | ENST00000338179.6 | c.1757G>A | p.Arg586His | missense_variant | 14/14 | 5 | P1 | ||
LBR | ENST00000441022.1 | n.232G>A | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
LBR | ENST00000651341.1 | c.*923G>A | 3_prime_UTR_variant, NMD_transcript_variant | 14/15 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151464Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251460Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135900
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461506Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 727104
GnomAD4 genome AF: 0.0000264 AC: 4AN: 151582Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 73964
ClinVar
Submissions by phenotype
Regressive spondylometaphyseal dysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 03, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 586 of the LBR protein (p.Arg586His). This variant is present in population databases (rs573510559, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive LBR-related conditions (PMID: 23824842, 34567078, 36307859). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 545626). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LBR protein function with a positive predictive value of 80%. This variant disrupts the p.Arg586 amino acid residue in LBR. Other variant(s) that disrupt this residue have been observed in individuals with LBR-related conditions (PMID: 30448303), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Greenberg dysplasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | Aug 28, 2022 | - - |
Pelger-Huët anomaly Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at