11-68935396-T-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_002180.3(IGHMBP2):āc.1730T>Gā(p.Leu577Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,016 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. L577P) has been classified as Pathogenic.
Frequency
Consequence
NM_002180.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 34
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461750Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727178
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152266Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74396
ClinVar
Submissions by phenotype
Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 13, 2022 | ClinVar contains an entry for this variant (Variation ID: 1066593). This missense change has been observed in individual(s) with IGHMBP2-related conditions (PMID: 25280635; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 577 of the IGHMBP2 protein (p.Leu577Arg). 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 IGHMBP2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu577 amino acid residue in IGHMBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14681881, 15108294, 22157136). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2024 | Variant summary: IGHMBP2 c.1730T>G (p.Leu577Arg) results in a non-conservative amino acid change located in the DNA2/NAM7 helicase-like, C-terminal domain (IPR041679) of 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 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1730T>G has been reported in the literature in at least one compound heterozygous individual affected with Autosomal Recessive Distal Spinal Muscular Atrophy 1 (Han_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25280635). ClinVar contains an entry for this variant (Variation ID: 1066593). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at