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RAB40AL – Martin-Probst syndrome

The association between RAB40AL and Martin-Probst syndrome has been reported in an initial case study where a p.Asp59Gly variant (c.176A>G) was identified in two unrelated affected males, with segregation noted in an X‑linked pedigree (PMID:24863632). However, subsequent multi‐patient analyses have raised serious concerns regarding the pathogenicity of this variant. These larger studies, which included screening of control populations (PMID:25044830, PMID:25370018, PMID:26300074), found a relatively high allele frequency of p.Asp59Gly in unaffected individuals, thereby challenging its causal role in the disorder.

In contrast, functional evidence demonstrates that the p.Asp59Gly variant disrupts RAB40AL function by destabilizing the protein and altering its subcellular localization, which is consistent with some features of the syndrome (PMID:22581972). Overall, while the functional data support a deleterious impact at the cellular level, the conflicting genetic data and the high prevalence of the variant in control cohorts render the gene‐disease association clinically disputed. Key take‑home: Cautious interpretation of RAB40AL p.Asp59Gly in clinical diagnostics is warranted, given its functional perturbation yet questionable disease specificity.

References

  • European journal of pediatrics • 2014 • Mutation in the X-linked RAB40AL gene (Martin-Probst syndrome) with mental retardation, sensorineural hearing loss, and anomalies of the craniofacies and genitourinary tract: a second case report PMID:24863632
  • Human mutation • 2014 • Evidence against RAB40AL being the locus for Martin-Probst X-linked deafness-intellectual disability syndrome PMID:25044830
  • European journal of pediatrics • 2015 • A note of caution on the diagnosis of Martin-Probst syndrome by the detection of the p.D59G mutation in the RAB40AL gene PMID:25370018
  • Molecular medicine reports • 2015 • Two‑gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome result PMID:26300074
  • Journal of medical genetics • 2012 • Disruption of RAB40AL function leads to Martin--Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder PMID:22581972

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Although an initial case report (PMID:24863632) identified the p.Asp59Gly variant with suggestive segregation, multiple independent studies (PMID:25044830, PMID:25370018, PMID:26300074) have shown a high prevalence of the variant in controls, undermining its pathogenic association.

Genetic Evidence

Limited

The genetic evidence is based on only two reported probands carrying the p.Asp59Gly variant, with conflicting segregation findings across studies.

Functional Evidence

Moderate

Functional assays demonstrated that the p.Asp59Gly variant impairs RAB40AL stability and cellular localization, aligning with aspects of the disease phenotype (PMID:22581972).