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Paediatric motor neuronopathies v3.20 SIGMAR1 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SIGMAR1.
Paediatric motor neuronopathies v3.20 SIGMAR1 Achchuthan Shanmugasundram Classified gene: SIGMAR1 as Amber List (moderate evidence)
Paediatric motor neuronopathies v3.20 SIGMAR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Luke Stuart, there is sufficient evidence available for the association of biallelic SIGMAR1 variants with distal hereditary motor neuronopathy 2. Hence, this gene can be promoted to green rating in the next GMS update.
Paediatric motor neuronopathies v3.20 SIGMAR1 Achchuthan Shanmugasundram Gene: sigmar1 has been classified as Amber List (Moderate Evidence).
Paediatric motor neuronopathies v3.19 SIGMAR1 Achchuthan Shanmugasundram Phenotypes for gene: SIGMAR1 were changed from ?Amyotrophic lateral sclerosis 16, juvenile 614373 to ?Neuronopathy, distal hereditary motor, autosomal recessive 2, OMIM:605726
Paediatric motor neuronopathies v3.18 SIGMAR1 Achchuthan Shanmugasundram Publications for gene: SIGMAR1 were set to 21842496
Paediatric motor neuronopathies v3.17 SIGMAR1 Luke Stuart changed review comment from: SIGMAR1 is associated with autosomal recessive distal hereditary motor neuronopathy 2 (OMIM: 605726) (accessed 10/ 2026)

Multiple unrelated patients and families with biallelic SIGMAR1 variants have been reported, typically presenting with early-onset, slowly progressive distal muscle weakness and atrophy, minimal or absent sensory involvement, and pyramidal signs (Li et al. 2015, PMID: 26078401; Lee et al. 2016, PMID: 28503617; Horga et al. 2016, PMID: 27629094; Ververis et al. 2020, PMID: 31511340). In the latter study, a homozygous missense mutation (c.500A>T, N167I) cosegregated with the dHMN phenotype in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. Recent evidence from six affected individuals in five unrelated Japanese families further supports biallelic SIGMAR1 variants as a cause of early-onset, motor-predominant axonal neuropathy with distal weakness and atrophy with pyramidal signs (Kodama et al. 2026, PMID: 42641169). Age of onset varied from <5 to 13 years of age.

Functional evidence supports impaired or reduced SIGMAR1 function as the disease mechanism. Loss of function variants including SIGMAR1 c.151+1G>T (a recurrent splicing variant) and c.500A>T, p.(Asn167Ile) have been described, the latter showing reduced protein expression, altered subcellular distribution and increased cell death (Li et al. 2015, PMID: 26078401; Ververis et al. 2020, PMID: 31511340).
Sigmar1-/- mice exhibit locomotor impairment, muscle weakness, axonal degeneration and motor-neuron loss, providing additional mechanistic support (Bernard-Marissal et al. 2015, PMID: 25678561)

A green rating is thus recommended for paediatric motor neuropathy.; to: SIGMAR1 is associated with autosomal recessive distal hereditary motor neuronopathy 2 (OMIM: 605726) (accessed 10/ 2026)

Multiple unrelated patients and families with biallelic SIGMAR1 variants have been reported, typically presenting with early-onset, slowly progressive distal muscle weakness and atrophy, minimal or absent sensory involvement, and pyramidal signs (Li et al. 2015, PMID: 26078401; Lee et al. 2016, PMID: 28503617; Horga et al. 2016, PMID: 27629094; Ververis et al. 2020, PMID: 31511340). In the latter study, a homozygous missense mutation (c.500A>T, N167I) cosegregated with the dHMN phenotype in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. Recent evidence from six affected individuals in five unrelated Japanese families further supports biallelic SIGMAR1 variants as a cause of early-onset, motor-predominant axonal neuropathy with distal weakness and atrophy with pyramidal signs (Kodama et al. 2026, PMID: 42641169). Age of onset varied from <5 to 13 years of age.

Functional evidence supports impaired or reduced SIGMAR1 function as the disease mechanism. Loss of function variants including SIGMAR1 c.151+1G>T (a recurrent splicing variant) and c.500A>T, p.(Asn167Ile) have been described, the latter showing reduced protein expression, altered subcellular distribution and increased cell death (Li et al. 2015, PMID: 26078401; Ververis et al. 2020, PMID: 31511340).
Sigmar1-/- mice exhibit locomotor impairment, muscle weakness, axonal degeneration and motor-neuron loss, providing additional mechanistic support (Bernard-Marissal et al. 2015, PMID: 25678561)

A green rating is thus recommended for paediatric motor neuronopathy.
Paediatric motor neuronopathies v3.17 SIGMAR1 Luke Stuart reviewed gene: SIGMAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26078401, 28503617, 27629094, 31511340, 42641169, 25678561; Phenotypes: ?Neuronopathy, distal hereditary motor, autosomal recessive 2 (OMIM:605726); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric motor neuronopathies SIGMAR1 Pinki Munot reviewed SIGMAR1
Paediatric motor neuronopathies SIGMAR1 Alice Gardham marked SIGMAR1 as ready
Paediatric motor neuronopathies SIGMAR1 Alice Gardham added SIGMAR1 to panel
Paediatric motor neuronopathies SIGMAR1 Alice Gardham reviewed SIGMAR1