Submissions for variant NM_003104.6(SORD):c.458C>A (p.Ala153Asp)

gnomAD frequency: 0.00033  dbSNP: rs145813597

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001311034	SCV001501057	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	SORD: PM3:Very Strong, PM2, PP1, PS3:Supporting
GeneDx	RCV001311034	SCV002104386	pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	In vitro assays demonstrated that A153D constructs transfected into HeLa cells formed misslocalized insoluble aggregates in the cytosol as compared to wild type (PMID: 33397963); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32367058, 33210134, 33369814, 34819907, 36431311, 35419909, 36943151, 33875678, 33397963)
3billion, Medical Genetics	RCV003152760	SCV003842138	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.045%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 33397963). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66;). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001012846 / PMID: 32367058). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 32367058). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Immunology and Genetics Kaiserslautern	RCV003152760	SCV004803218	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2024-03-06	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PM2_P, PM3, PP3, PP4, PP5; Variant was found in heterozygous state
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003152760	SCV004806609	likely pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004034236	SCV004957641	uncertain significance	Inborn genetic diseases	2020-06-05	flagged submission	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.458C>A (p.A153D) alteration is located in coding exon 5 of the SORD gene. This alteration results from a C to A substitution at nucleotide position 458, causing the alanine (A) at amino acid position 153 to be replaced by an aspartic acid (D). The alteration has been observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.458C>A alteration was observed in 0.0453% (128/282740) of total alleles studied, with a frequency of 0.635% (82/129066) in the European (non-Finnish) subpopulation. No homozygotes were observed. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been observed to co-occur with a pathogenic mutation in two affected individuals from one family. Common clinical features were walking difficulties and an intermediate reduction of nerve conduction velocities. One patient further developed upper limb weakness and tremor (Cortese, 2020). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.A153 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.A153D alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.