chr16-81357902-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4
The NM_022041.4(GAN):c.944C>T(p.Pro315Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000202 in 1,613,632 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. P315R) has been classified as Uncertain significance.
Frequency
Consequence
NM_022041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.944C>T | p.Pro315Leu | missense_variant | 5/11 | ENST00000648994.2 | |
GAN | NM_001377486.1 | c.305C>T | p.Pro102Leu | missense_variant | 4/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.944C>T | p.Pro315Leu | missense_variant | 5/11 | NM_022041.4 | P1 | ||
GAN | ENST00000648349.2 | c.*652C>T | 3_prime_UTR_variant, NMD_transcript_variant | 4/10 | |||||
GAN | ENST00000650388.1 | c.*301C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/9 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251490Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135918
GnomAD4 exome AF: 0.000211 AC: 309AN: 1461516Hom.: 2 Cov.: 31 AF XY: 0.000202 AC XY: 147AN XY: 727114
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74296
ClinVar
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 315 of the GAN protein (p.Pro315Leu). This variant is present in population databases (rs144486241, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with giant axonal neuropathy (PMID: 14718689, 17578852; Invitae). 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: 245843). 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 not expected to disrupt GAN protein function with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The GAN c.944C>T (p.Pro315Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two patients with giant axonal neuropathy, one with a missense variant on the second allele, and one with a frameshift variant (Bruno et al. 2004; Houlden et al. 2007). The p.Pro315Leu variant was also found in a heterozygous state in one of the parents diagnosed with mild multiple sclerosis. The p.Pro315Leu variant was absent from 100 controls but is reported at a frequency of 0.000907 in the European (Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Pro315Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for giant axonal neuropathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2021 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17256086, 17578852, 14718689, 21356581, 23890932) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2022 | The p.P315L variant (also known as c.944C>T), located in coding exon 5 of the GAN gene, results from a C to T substitution at nucleotide position 944. The proline at codon 315 is replaced by leucine, an amino acid with similar properties. In one individual with giant axonal neuropathy, this alteration was detected in trans with a frameshift alteration in GAN (Houlden H et al. J Neurol Neurosurg Psychiatry, 2007 Nov;78:1267-70). This alteration was also detected as compound heterozygous with a missense alteration in GAN In another individual with giant axonal neuropathy; however, the phase of the variants was unknown (Bruno C et al. Neurology, 2004 Jan;62:13-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Giant axonal neuropathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Neurogenomics Lab, Neuroscience Institute, University Of Cape Town | May 22, 2024 | PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.0008910 (0.089%; 57/63974 alleles in European Finnish population) and in gnomAD v3.1.2 is 0.0007556 (0.076%; 1/10588 alleles in European Finnish population) and the variant is absent from an internal database of 1074 alleles. PS4_supporting: variant identified in 2 unrelated probands with consistent phenotype for disorder (PMID 14718689, PMID 17578852). PP3 not met: REVEL score is 0.49. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at