Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000412506 | SCV001381774 | pathogenic | Neuropathy, hereditary motor and sensory, type 6B | 2022-05-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 340 of the SLC25A46 protein (p.Arg340Cys). This variant is present in population databases (rs746681765, gnomAD 0.005%). This missense change has been observed in individuals with SLC25A46-related conditions (PMID: 26168012, 28369803, 28558379). This variant is also known as R259C. ClinVar contains an entry for this variant (Variation ID: 372242). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC25A46 function (PMID: 27543974). For these reasons, this variant has been classified as Pathogenic. |
Neurometabolic Diseases Laboratory, |
RCV000412506 | SCV003920817 | pathogenic | Neuropathy, hereditary motor and sensory, type 6B | 2023-04-27 | criteria provided, single submitter | research | |
Clinical Genomics Laboratory, |
RCV003458425 | SCV004177010 | pathogenic | Neuropathy, hereditary motor and sensory, type 6B; Pontocerebellar hypoplasia, type 1E | 2023-09-08 | criteria provided, single submitter | clinical testing | The SLC25A46 c.1018C>T (p.Arg340Cys) variant has been reported in nine individuals across three consanguineous families affected with hereditary motor and sensory neuropathy type VIB (Abrams AJ et al., PMID: 26168012; Hammer MB et al., PMID: 28558379; Sulaiman RA et al., PMID: 28369803). Functional studies show less abundant protein expression compared to wild type, indicating that this variant impacts protein stability (Wan J et al., PMID: 27543974). This variant is only observed in 7 alleles out of 250,792 total alleles in the general population, including no homozygotes (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to SLC25A46 function. This variant has been reported in the ClinVar database as a pathogenic variant by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. |
OMIM | RCV000412506 | SCV000490317 | pathogenic | Neuropathy, hereditary motor and sensory, type 6B | 2023-02-14 | no assertion criteria provided | literature only |