Submissions for variant NM_003104.6(SORD):c.757del (p.Ala253fs)

dbSNP: rs55901542

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001266105	SCV001444277	pathogenic	Inborn genetic diseases	2020-06-05	criteria provided, single submitter	clinical testing	The c.757delG (p.A253Qfs*27) alteration, located in coding exon 7 of the SORD gene, results from a deletion of one nucleotide at position 757, causing a translational frameshift with a predicted alternate stop codon after 27 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the SORD c.757delG (p.A253Qfs*27) alteration was observed in 0.0415% (115/277,146) of total alleles studied, with a frequency of 0.0613% (15/24,486) in the African subpopulation. One homozygote was observed. This alteration has been observed homozygous in 38 families and compound heterozygous with a second alteration in 7 families affected with neuropathy (Cortese, 2020). Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001311035	SCV001501058	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	SORD: PVS1, PM2, PM3, PS3:Supporting
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001194463	SCV001737015	likely pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8		criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814278	SCV001755401	likely pathogenic	Peripheral neuropathy	2021-07-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001311035	SCV001905646	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001311035	SCV002008398	pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32367057, 32367058, 33381078, 33314640)
Revvity Omics, Revvity	RCV001194463	SCV002020777	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2023-12-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194463	SCV002041655	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2021-11-16	criteria provided, single submitter	clinical testing	Variant summary: SORD c.757delG (p.Ala253GlnfsX27) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00041 in 277146 control chromosomes in the gnomAD v2.1.1 database, including 1 homozygote. However, this observation needs to be cautiously considered due to the possibility of the SORD pseudogene being captured. c.757delG has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with hereditary neuropathy (e.g. Cortese_2020, Xie_2020, Dong_2021, Lassuthova_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant causes a significant reduction in SORD mRNA expression levels and protein levels, indicating a NMD mechanism and loss of function of the SORD gene (Cortese_2020, Dong_2021). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001311035	SCV002051717	pathogenic	not provided	2021-01-04	criteria provided, single submitter	clinical testing	PVS1, PP1, PM3
3billion	RCV001194463	SCV002058953	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32367058, PS3_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000929258, PMID:32367058, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000415, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 32367058, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001194463	SCV002576404	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2023-11-16	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_VSTR,PS3,PP4; Identified as compund heterozygous with NM_003104.6:c.50C>T
MGZ Medical Genetics Center	RCV001194463	SCV002581404	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-06-28	criteria provided, single submitter	clinical testing
Nutriplexity	RCV002468945	SCV002756471	pathogenic	Idiopathic environmental intolerance	2022-11-29	criteria provided, single submitter	clinical testing	The SORD gene encodes sorbitol dehydrogenase which oxidizes sorbitol to fructose using NAD+. Elevations of blood glucose result in high blood and tissue sorbitol levels. Sorbitol build-up results in the depletion of glutathione (PMID 8622605). An altered redox profile and depletion of glutathione is characteristic of chemical sensitivity (20430047).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001194463	SCV002768053	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with sorbitol dehydrogenase deficiency with peripheral neuropathy (MIM#618912). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (661 heterozygotes, 1 homozygote). (SP) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. At least four others have been reported so far (ClinVar, PMID: 32367058, 33875678). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (ClinVar) and reported in over thirty unrelated families with hereditary neuropathy (PMID: 32367058). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001194463	SCV003807286	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-03-30	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PM3 strong, PP1 moderated
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001311035	SCV004026086	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing	PVS1, PS3
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001194463	SCV004046250	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 7 of 9 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous and homozygous change in patients with sorbitol dehydrogenase deficiency with peripheral neuropathy (PMID: 32367057, 32367058, 33381078, 33314640). The c.757del (p.Ala253GlnfsTer27) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.041% (115/277146) and in the homozygous state in 1 individual. Experimental studies showed that this variant reduces SORD mRNA expression and protein levels (PMID: 33397963, 32367058). Based on the available evidence, the c.757del (p.Ala253GlnfsTer27) variant is classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001194463	SCV004171966	likely pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8		criteria provided, single submitter	clinical testing	The frameshift c.757del(p.Ala253GlnfsTer27) variant in SORD gene has been reported previously in homozygous and compound heterozygous state in patients affected with neuropathy (Laššuthová, P., et al.,2021; Liu X, et. al.,2021). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (Cortese A, et. al.,2020). The p.Ala253GlnfsTer27 variant is reported with an allele frequency of 0.008% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain significance/ Likely pathogenic/ Pathogenic (multiple submission). This variant causes a frameshift starting with codon Alanine 253, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Ala253GlnfsTer27. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV001194463	SCV004175344	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-10-17	criteria provided, single submitter	clinical testing	The SORD c.757del variant is classified as PATHOGENIC (PVS1, PS2, PS3, PS4) This SORD c.757del variant is located in exon 7/9 and is predicted to cause a shift in the reading frame at codon 253. This variant has been identified as a de novo variant in this patient (PS2). This recurrent variant has been reported in multiple probands with a clinical presentation of hereditary neuropathy in both homozygous and compound heterozygous state (PMID:32367058; PMID:33875678; PMID:33381078). (PS4, PM3). Functional studies have shown a significant reduction in SORD mRNA and protein levels (PMID:32367058) (PS3). This variant has been reported in dbSNP (rs55901542) and in the HGMD database: CD2011533. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 929258).
Mayo Clinic Laboratories, Mayo Clinic	RCV001311035	SCV004224023	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	PP4, PM3, PS3, PS4, PVS1
Institute of Immunology and Genetics Kaiserslautern	RCV001194463	SCV004803217	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2024-03-06	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM3, PP4, PP5; Variant was found in heterozygous state
OMIM	RCV001194463	SCV001364049	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2023-10-17	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001194463	SCV001760348	likely pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8		no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV001194463	SCV001827226	uncertain significance	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-07-15	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001194463	SCV002583442	pathogenic	Neuronopathy, distal hereditary motor, autosomal recessive 8	2022-05-02	no assertion criteria provided	clinical testing