ClinVar Miner

Submissions for variant NM_000454.4(SOD1):c.272A>C (p.Asp91Ala) (rs80265967)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000713399 SCV000329527 uncertain significance not provided 2016-01-29 criteria provided, single submitter clinical testing The D91A variant in the SOD1 gene has been reported multiple times, using alternate nomenclature (D90A), in association with familial ALS. When found in the homozygous and compound heterozygous state D91A has been reported as a disease-associated variant (Hand et al., 2001; Andersen et al., 1995; Felbecker et al., 2010). However, in the heterozygous state the pathogenicity of the the D91A variant is debated (Al-Chalabi et al., 1998; Felbecker et al., 2010). The D91A variant is found with significant frequency among Scandinavian populations (Al-Chalabi et al., 1998); and the NHLBI ESP Exome Sequencing Project reports D91A was observed at a frequency of 0.08%, 7/8600 alleles, from individuals of European ancestry, indicating it may be a rare variant in this population. The D91A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. Functional studies suggest that the D91A variant may not alter protein activity and stability to the same degree as other established SOD1 variants associated with familial ALS (Själander et al., 1995; Fujisawa et al., 2012; Lindberg et al., 2002). Given the available information, we interpret D91A as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000290605 SCV000435555 likely benign Amyotrophic Lateral Sclerosis, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000015888 SCV000597223 likely pathogenic Amyotrophic lateral sclerosis type 1 2016-12-12 criteria provided, single submitter clinical testing
Invitae RCV000015888 SCV000766153 uncertain significance Amyotrophic lateral sclerosis type 1 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 91 of the SOD1 protein (p.Asp91Ala). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs80265967, ExAC 1.0%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals and several families affected with amyotrophic lateral sclerosis (ALS) in the homozygous state (PMID: 7647793, 20460594, 22264771, 18608106, 10809943, 14506936, 19703565, 11369193, 11284995, 23062701), compound heterozygous state (PMID: 23280792, 11220750) and in the heterozygous state (PMID: 19922148, 22264771, 10809943, 14506936, 8909456). This variant has also been reported in unaffected individuals in the heterozygous state (PMID: 20460594, 7647793, 11369193). This variant is also known as p.Asp90Ala in the literature. ClinVar contains an entry for this variant (Variation ID: 14766). Experimental studies have shown that this missense change affects protein function (PMID: 22264771, 19703565, 18319614, 16945901, 19635794, 12482932, 25509359, 25792239, 7655469, 17420412, 20189984). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000713399 SCV000844000 pathogenic not provided 2020-05-18 criteria provided, single submitter clinical testing This variant is also referred to as p.Asp90Ala in published literature. This is a founder variant with reported recessive and dominant disease inheritance (PMID 12442272), and so its frequency in the general population is consistent with pathogenicity. This variant associates with disease in multiple families reported to exhibit both autosomal dominant and autosomal recessive inheritance. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Mendelics RCV000015888 SCV001141287 uncertain significance Amyotrophic lateral sclerosis type 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000713399 SCV001153538 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University RCV000015888 SCV001251054 likely pathogenic Amyotrophic lateral sclerosis type 1 2020-03-31 criteria provided, single submitter research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000713399 SCV001448077 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000713399 SCV001715589 uncertain significance not provided 2019-10-14 criteria provided, single submitter clinical testing
OMIM RCV000015888 SCV000036155 pathogenic Amyotrophic lateral sclerosis type 1 2007-04-10 no assertion criteria provided literature only
OMIM RCV000015889 SCV000036156 pathogenic Amyotrophic lateral sclerosis 1, autosomal recessive 2007-04-10 no assertion criteria provided literature only
Institute of Human Genetics,Cologne University RCV000015888 SCV000787782 pathogenic Amyotrophic lateral sclerosis type 1 2018-04-25 no assertion criteria provided clinical testing

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