rs387906829
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_005866.4(SIGMAR1):āc.304G>Cā(p.Glu102Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,908 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 Pathogenic (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_005866.4 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 |
---|---|---|---|---|---|---|---|
SIGMAR1 | NM_005866.4 | c.304G>C | p.Glu102Gln | missense_variant | 2/4 | ENST00000277010.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SIGMAR1 | ENST00000277010.9 | c.304G>C | p.Glu102Gln | missense_variant | 2/4 | 1 | NM_005866.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1419908Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1AN XY: 703908
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2020 | The p.E102Q variant (also known as c.304G>C), located in coding exon 2 of the SIGMAR1 gene, results from a G to C substitution at nucleotide position 304. The glutamic acid at codon 102 is replaced by glutamine, an amino acid with highly similar properties. In a large consanguineous family with Middle Eastern ancestry, this variant was reported in the homozygous state and found to segregate with disease in multiple relatives with juvenile amyotrophic lateral sclerosis (Al-Saif A et al. Ann Neurol, 2011 Dec;70:913-9). This variant impacts a region critical to protein function, and several functional studies demonstrate abnormal protein function including mislocalization, aggregation, impaired signaling and reduced cell survival (Al-Saif A et al. Ann Neurol, 2011 Dec;70:913-9; Fukunaga K et al. J Pharmacol Sci, 2015 Jan;127:36-41; Schmidt HR et al. Nature, 2016 Apr;532:527-30; Watanabe S et al. EMBO Mol Med, 2016 12;8:1421-1437; Dreser A et al. Cell Death Differ, 2017 10;24:1655-1671; Abramyan AM et al. Comput Struct Biotechnol J, 2020 Jan;18:199-206; Couly S et al. Hum Mol Genet, 2020 03;29:529-540; Rodríguez-Muñoz M et al. Int J Mol Sci, 2020 Oct;21:7339). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Autosomal recessive distal spinal muscular atrophy 2;C3280587:Amyotrophic lateral sclerosis type 16 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SIGMAR1 function (PMID: 21842496, 25175561, 25704016, 27821430, 28622300, 31696229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 30238). This missense change has been observed in individual(s) with juvenile amyotrophic lateral sclerosis (PMID: 21842496). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 102 of the SIGMAR1 protein (p.Glu102Gln). - |
Amyotrophic lateral sclerosis type 16 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at