SORD

protein-coding

sorbitol dehydrogenase

Gene summary

Sorbitol dehydrogenase (SORD; EC 1.1.1.14) catalyzes the interconversion of polyols and their corresponding ketoses, and together with aldose reductase (ALDR1; MIM 103880), makes up the sorbitol pathway that is believed to play an important role in the development of diabetic complications (summarized by Carr and Markham, 1995 [PubMed 8535074]). The first reaction of the pathway (also called the polyol pathway) is the reduction of glucose to sorbitol by ALDR1 with NADPH as the cofactor. SORD then oxidizes the sorbitol to fructose using NAD(+) cofactor.[supplied by OMIM, Jul 2010]

MANE transcript

NM_003104.6

Inheritance

ClinVar variants

P:14U:71B:30

Top phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 8

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr15:45,023,147-45,077,185

External References & Databases

Ensembl (ENSG00000140263)

Transcript & Mutation Effects

hg38 • Region Span ~54.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronopathy, distal hereditary motor, autosomal recessive 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030055

Submitter: PanelApp Australia

Charcot-Marie-Tooth diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: ClinGen

SORD was first reported in relation to autosomal recessive Charcot-Marie-Tooth disease (CMT) in 2020 (Cortese et al., PMID: 32367058). SORD neuropathy (OMIM: 618912) is caused by loss of the enzyme sorbitol dehydrogenase, which converts sorbitol to fructose, leading to toxic accumulation of sorbitol levels. Patients with SORD variants develop CMT2 or distal hereditary motor neuropathy (dHMN). SORD deficiency is one of the most common types of recessive CMT, with an estimated prevalence of 1 to 100,000 individuals. In this curation, we have included 5 probands from three different publications, all harboring a common frameshift variant (Ala253GlnfsTer27), presented as homozygous or compound heterozygous (PMID: 32367058, 34995833, and 33875678). The most common pathogenic variant is present at a relatively high allele frequency in the population (gnomAD= 0.0004). More evidence is available in the literature, but the maximum score for the genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease association is also supported by experimental evidence (expression studies, animal model, and functional alteration in patient cells)(PMID: 32367058 and 9604875). Fibroblasts and serum from patients show abnormally increased levels of sorbitol. Loss of the SORD gene ortholog in Drosophila caused synaptic degeneration, progressive motor impairment, and increased sorbitol levels, which were rescued by treatment with aldose reductase inhibitors (PMID: 32367058). A total of 15.5 points have been obtained for this curation. In summary, SORD is definitively associated with autosomal recessive CMT. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

neuronopathy, distal hereditary motor, autosomal recessive 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030055

Submitter: Labcorp Genetics (formerly Invitae)

neuronopathy, distal hereditary motor, autosomal recessive 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030055

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neuronopathy, distal hereditary motor, autosomal recessive 8AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 32367058

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SORD variants in ClinVar

8 Conditions Cataloged

not providedTotal: 56

Inborn genetic diseasesTotal: 54

Neuronopathy, distal hereditary motor, autosomal recessive 8Total: 19

not specifiedTotal: 18

SORD-related disordersTotal: 2

Idiopathic environmental intoleranceTotal: 1

Neuromuscular diseaseTotal: 1

Autosomal recessive distal spinal muscular atrophy 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003104.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	17 clinvar	6 clinvar	24
missense	1 clinvar	5 clinvar	66 clinvar	5 clinvar	2 clinvar	79
nonsense	2 clinvar	2 clinvar				4
start loss						0
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	4	10	71	22	8	115

Highest pathogenic variant AF is 0.0031969629

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003104.6	RefSeq	NP_003095.2	9	MANE Select
ENST00000267814.14	Ensembl	ENSP00000267814.9	9	MANE Select
ENST00000558789.5	Ensembl	ENSP00000453904.1	4	Standard
ENST00000559230.5	Ensembl	ENSP00000452731.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fructose and mannose metabolism - Homo sapiens (human)
Pentose and glucuronate interconversions - Homo sapiens (human)
Fructose intolerance, hereditary
Fructose and Mannose Degradation
Fructosuria

Biological Process

glucose metabolic process
sorbitol catabolic process
response to osmotic stress
response to hormone
glucuronate catabolic process to xylulose 5-phosphate

Molecular Function

L-iditol 2-dehydrogenase activity
zinc ion binding
carbohydrate binding
identical protein binding
D-xylulose reductase activity

Cellular Component

extracellular space
cytosol
membrane
motile cilium
mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000267814
Coding exons: 9
Length: 54082
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 125748
p: 0.000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.351	185	172	1.08	0.00000953	2254
Missense (PolyPhen)		62	62.735	0.98829		746
Synonymous	-0.588	75	68.8	1.09	0.00000406	729
Loss of Function	0.739	13	16.2	0.802	0.00000104	204

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.00081	0.00078	rare
Ashkenazi Jewish	0.00024	0.00020	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00027	0.00026	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Converts sorbitol to fructose. Part of the polyol pathway that plays an important role in sperm physiology. May play a role in the sperm motility by providing an energetic source for sperm. {ECO:0000250|UniProtKB:Q64442, ECO:0000269|PubMed:16278369}.;

Recessive Scores

pRec: 0.603

Intolerance Scores

LoFtool: 0.766
RVIS EVS: 0.86
RVIS percentile EVS: 88.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.607

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium