VCV000929258.74 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(29)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 929258 Accession: VCV000929258.74

Type and length

Deletion, 1 bp

Location

Cytogenetic: 15q21.1 15: 45069019 (GRCh38) [ NCBI UCSC ] 15: 45361217 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 22, 2020	Oct 26, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003104.6:c.757del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003095.2:p.Ala253fs	frameshift
NM_003104.6:c.757delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_003104.5:c.757del
NR_034039.2:n.931del		non-coding transcript variant
NC_000015.10:g.45069023del
NC_000015.9:g.45361221del

... more HGVS ... less HGVS

Protein change

A253fs

Other names

p.A253Qfs*27
p.Ala253Glnfs*27

Canonical SPDI

NC_000015.10:45069018:GGGGG:GGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

protein truncation; Variation Ontology [ VariO:0015]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 182500.0001 dbSNP: rs55901542 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SORD		-	-	GRCh38 GRCh37	97	123

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 5, 2020	RCV001266105.6
Neuromuscular disease	Pathogenic (1)	criteria provided, single submitter	Jan 27, 2021	RCV004017799.2
Neuronopathy, distal hereditary motor, autosomal recessive 8	Pathogenic/Likely pathogenic (19)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV001194463.34
Idiopathic environmental intolerance	Pathogenic (1)	criteria provided, single submitter	Nov 29, 2022	RCV002468945.3
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV001311035.28
Peripheral neuropathy	Likely pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001814278.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001905646.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Clinical Features: Spastic paraplegia (present) Sex: male
Pathogenic (Nov 16, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002041655.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021	Publications: PubMed (4) PubMed: 32367058‚ 33397963‚ 33875678‚ 33381078 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: germline	3billion Accession: SCV002058953.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:32367058 PMID:32367058 Comment: 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 … (more) 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. (less) Clinical Features: Cough (present) , Frequent falls (present) , Gait ataxia (present) , Muscle weakness (present) , Peripheral axonal degeneration (present) , Abnormal peripheral nervous system morphology … (more) Cough (present) , Frequent falls (present) , Gait ataxia (present) , Muscle weakness (present) , Peripheral axonal degeneration (present) , Abnormal peripheral nervous system morphology (present) , Urinary bladder sphincter dysfunction (present) (less)
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002051717.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022	Comment: PVS1, PP1, PM3
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002008398.2 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Dec 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020777.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jun 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581404.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM3_VSTR, PS3_MOD, PS4_MOD, PM2_SUP	Number of individuals with the variant: 9 Sex: female
Pathogenic (Nov 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002576404.2 First in ClinVar: Oct 01, 2022 Last updated: Dec 17, 2023	Comment: Criteria applied: PVS1,PM3_VSTR,PS3,PP4; Identified as compund heterozygous with NM_003104.6:c.50C>T Clinical Features: Generalized hypotonia (present) , Progressive distal muscle weakness (present) , Motor axonal neuropathy (present) Sex: male
Pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Idiopathic environmental intolerance (Semidominant inheritance) Affected status: yes Allele origin: unknown	Nutriplexity Accession: SCV002756471.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 8622605 Comment: 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. … (more) 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). (less) Clinical Features: Multiple chemical sensitivity (present) , Headaches (present) , Low glutathione (present) Sex: male Geographic origin: American Testing laboratory: Nebula Genomics
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768053.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 32367058‚ 33875678 Comment: 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 … (more) 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 (less)
Pathogenic (Jun 05, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001444277.4 First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 32367058‚ 32457452‚ 33201363 Comment: The c.757delG (p.A253Qfs27) alteration, located in coding exon 7 of the SORD gene, results from a deletion of one nucleotide at position 757, causing a … (more) The c.757delG (p.A253Qfs27) 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. (less)
Pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001501058.21 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: SORD: PM3:Very Strong, PVS1, PP1:Strong, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 16
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001737015.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 Comment: Homozygous, both variants are inherited from each parent
Likely pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peripheral neuropathy Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755401.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807286.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS3 supporting, PM3 strong, PP1 moderated Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Jul 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026086.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1, PS3
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sorbitol dehydrogenase deficiency with peripheral neuropathy Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046250.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Oct 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175344.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (3) PubMed: 32367058‚ 33381078‚ 33875678 Comment: 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 … (more) 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). (less)
Pathogenic (Jan 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224023.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 32367058‚ 33397963‚ 33875678 Comment: PP4, PM3, PS3, PS4, PVS1 Number of individuals with the variant: 4
Pathogenic (Mar 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV004803217.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: ACMG Criteria: PVS1, PM3, PP4, PP5; Variant was found in heterozygous state Clinical Features: Distal amyotrophy (present) , Poor fine motor coordination (present) , Tremor (present) , Paresthesia (present)
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806857.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Jan 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuromuscular disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848480.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (2) PubMed: 33397963‚ 32367058 Comment: The p.Ala253GlnfsX27 variant in SORD has been reported in European, East Asian, and Egyptian individuals with clinical diagnoses of Charcot-Marie-Tooth disease 2 or distal hereditary … (more) The p.Ala253GlnfsX27 variant in SORD has been reported in European, East Asian, and Egyptian individuals with clinical diagnoses of Charcot-Marie-Tooth disease 2 or distal hereditary neuropathy, all of whom were homozygous or also carried a second SORD variant. This variant also segregated with disease in 7 affected individuals from 6 families (Cortese 2020, PMID: 32367058; Dong 2021, PMID: 33397963). The p.Ala253GlnfsX27 variant has been identified in 0.06% (15/24486) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has also been reported in ClinVar (Variation ID: 929258). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 253 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SORD gene is strongly associated with autosomal recessive sorbitol dehydrogenase deficiency with peripheral neuropathy. In vitro functional studies support an impact on protein function (Cortese 2020, PMID: 32367058; Dong 2021, PMID: 33397963). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive sorbitol dehydrogenase deficiency with peripheral neuropathy. ACMG/AMP Criteria applied: PVS1_Strong, PP1_Strong, PM3, PS3_Moderate. (less)
Likely pathogenic (Dec 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005049382.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004171966.2 First in ClinVar: Dec 09, 2023 Last updated: Jul 15, 2024	Comment: The frameshift variant c.757del (p.Ala253GlnfsTer27) in the SORD gene has been reported previously in homozygous state in individuals affected with distal hereditary motor neuropathy and … (more) The frameshift variant c.757del (p.Ala253GlnfsTer27) in the SORD gene has been reported previously in homozygous state in individuals affected with distal hereditary motor neuropathy and Charcot-Marie-Tooth disease (Alluqmani et al., 2022; Yuan et al., 2021). This variant is reported with the allele frequency (0.04%) in the gnomAD Exomes. It has been submitted to ClinVar as Pathogenic/ Likely Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. (less) Clinical Features: Abnormality of the musculoskeletal system (present)
Uncertain significance (Jul 15, 2022)	no assertion criteria provided Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: unknown	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001827226.2 First in ClinVar: Sep 08, 2021 Last updated: Jan 15, 2023 Comment: VARIANT DETAILS The c.583-3C>A variant in the PLS3 gene has not been described in ClinVar. This variant has not been observed in gnomAD. This splicing … (more) VARIANT DETAILS The c.583-3C>A variant in the PLS3 gene has not been described in ClinVar. This variant has not been observed in gnomAD. This splicing region variant is predicted to alter splicing (SpliceAI: 0.900). This variant has not been detected in the parental samples of this individual by whole genome sequencing analysis, suggesting that this change arose de novo in the patient. However, the possibility of low level mosaicism in either parent cannot be excluded. (less)	Number of individuals with the variant: 1 Clinical Features: Sensory neuropathy (present) , Elevated circulating creatine kinase concentration (present) , Steppage gait (present) , EMG: axonal abnormality (present) , Motor axonal neuropathy (present) , … (more) Sensory neuropathy (present) , Elevated circulating creatine kinase concentration (present) , Steppage gait (present) , EMG: axonal abnormality (present) , Motor axonal neuropathy (present) , Lower limb muscle weakness (present) , Exercise-induced rhabdomyolysis (present) , Peroneal muscle atrophy (present) (less) Age: 70-79 years Sex: male Tissue: Blood
Pathogenic (Oct 17, 2023)	no assertion criteria provided Method: literature only	NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001364049.4 First in ClinVar: Jun 22, 2020 Last updated: Oct 21, 2023	Publications: PubMed (2) PubMed: 32367058‚ 34819907 Comment on evidence: In affected individuals from 30 unrelated families with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912), also known as SORD deficiency with peripheral neuropathy (SORDD), … (more) In affected individuals from 30 unrelated families with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912), also known as SORD deficiency with peripheral neuropathy (SORDD), Cortese et al. (2020) identified a homozygous 1-bp deletion (c.757delG, NM_003104.6) in exon 7 of the SORD gene, predicted to result in a frameshift and premature termination (Ala253GlnfsTer27) in the tetramer interface of the protein. Segregation of the variant was confirmed in only a few families in which the affected offspring inherited the variants from heterozygous unaffected parents, and only a few families had more than 1 affected individual. The mutation was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. The variant was present in 623 of 142,588 genomes in the gnomAD database (frequency of 0.004). Cortese et al. (2020) noted that SORD has a nonfunctional highly homologous paralog, the pseudogene SORD2 or SORD2P: the c.757delG variant is present in SORD2 in over 95% of control chromosomes. The authors used Sanger sequencing to confirm that the c.757delG mutation identified in their patients occurred in the SORD gene. Fibroblasts derived from 4 patients who were homozygous for the c.757delG variant showed absence of the SORD protein and a 10-fold increase in intracellular sorbitol compared to controls. Treatment of patient fibroblasts with aldose reductase inhibitors reduced intracellular sorbitol levels. Additional functional studies of the specific variants were not performed. Serum levels of sorbitol were over 100 times higher in 10 patients with the homozygous variant compared to controls. Eight additional patients, including 2 sibs (family 14), with a similar phenotype were compound heterozygous for c.757delG and another SORD variant. The other alleles included R299X (182500.0002), R110P, R100X, A153D, V322I, L10F, and an intragenic deletion (c.316_425+165del). Familial segregation of these variants could be demonstrated in only 2 patients (patients 4 and 37); familial segregation could not be conclusively demonstrated in the other patients. Several of these variants were present in the gnomAD database at a low frequency (less than 0.0001). All patients were ascertained from 3 large cohorts totaling about 1,000 individuals with peripheral neuropathy who underwent whole-exome or whole-genome sequencing. In 2 unrelated Chinese patients (patients 1 and 2) with SORDD, Liu et al. (2021) identified homozygosity for the c.757delG mutation in the SORD gene. The mutation, which was identified by whole-exome sequencing, was identified in the carrier state in both sets of parents. The mutation was present at a frequency of 0.0046 in 650 Han Chinese healthy individuals and at a frequency of 0.002 in the Asian population in the gnomAD database (v3.0); it was not present in the 1000 Genomes Project database. In 3 additional unrelated Chinese patients with SORDD, Liu et al. (2021) identified compound heterozygosity for the c.757delG mutation with another mutation in the SORD gene: a c.776C-T transition, resulting in an ala259-to-val (A259V; 182500.0003) substitution, in patient 3; a c.731C-T transition, resulting in a pro244-to-leu (182500.0004) substitution, in patient 4; and a c.851T-C transition, resulting in a leu284-to-pro (L284P; 182500.0005) substitution, in patient 5. The parents in each case were carriers. The missense variants in patients 3, 4, and 5 occurred at highly conserved residues and had a minor allele frequency of less than 0.00001 in gnomAD (v3.0). All 3 variants were classified as likely pathogenic according to ACMG guidelines. (less)
Pathogenic (May 02, 2022)	no assertion criteria provided Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002583442.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760348.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Neuronopathy, distal hereditary motor, autosomal recessive 8 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005200013.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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).

Comment:

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

Comment:

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.

Comment:

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.

Comment:

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).

Comment:

The p.Ala253GlnfsX27 variant in SORD has been reported in European, East Asian, and Egyptian individuals with clinical diagnoses of Charcot-Marie-Tooth disease 2 or distal hereditary neuropathy, all of whom were homozygous or also carried a second SORD variant. This variant also segregated with disease in 7 affected individuals from 6 families (Cortese 2020, PMID: 32367058; Dong 2021, PMID: 33397963). The p.Ala253GlnfsX27 variant has been identified in 0.06% (15/24486) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has also been reported in ClinVar (Variation ID: 929258). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 253 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SORD gene is strongly associated with autosomal recessive sorbitol dehydrogenase deficiency with peripheral neuropathy. In vitro functional studies support an impact on protein function (Cortese 2020, PMID: 32367058; Dong 2021, PMID: 33397963). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive sorbitol dehydrogenase deficiency with peripheral neuropathy. ACMG/AMP Criteria applied: PVS1_Strong, PP1_Strong, PM3, PS3_Moderate.

Comment:

The frameshift variant c.757del (p.Ala253GlnfsTer27) in the SORD gene has been reported previously in homozygous state in individuals affected with distal hereditary motor neuropathy and Charcot-Marie-Tooth disease (Alluqmani et al., 2022; Yuan et al., 2021). This variant is reported with the allele frequency (0.04%) in the gnomAD Exomes. It has been submitted to ClinVar as Pathogenic/ Likely Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
protein truncation (VariO:0015)			Nutriplexity Accession: SCV002756471.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy.	Liu X	Frontiers in neurology	2021	PMID: 34819907
Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients.	Laššuthová P	Scientific reports	2021	PMID: 33875678
Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy.	Dong HL	NPJ genomic medicine	2021	PMID: 33397963
Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families.	Xie Y	Frontiers in neurology	2020	PMID: 33381078
Author Correction: Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.	Cortese A	Nature genetics	2020	PMID: 32457452
Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.	Cortese A	Nature genetics	2020	PMID: 32367058
Relationship between glutathione and sorbitol concentrations in erythrocytes from diabetic patients.	Ciuchi E	Metabolism: clinical and experimental	1996	PMID: 8622605
-	-	-	-	PMID: 33201363

Text-mined citations for rs55901542 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs55901542 ...