ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.-17G>A (rs879254047)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235476 SCV000293293 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing The c.-17 G>A variant (also reported as c.-373 G>A using alternative nomenclature) alters the last base of exon 1 in the 5' UTR and has been reported to segregate with CMTX1 in two families (Murphy et al., 2011). It was also reported as a pathogenic variant in another patient with CMT1X (Arthur-Farraj et al., 2012). This substitution occurs at a position that is conserved in mammals. Data from control individuals were not available to assess whether this variant may be a common benign variant in the general population. The c.-17 G>A variant is immediately adjacent to the canonical donor site in intron 1; however, in silico analysis predicts this variant likely does not alter splicing. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000470682 SCV000544774 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-11-12 criteria provided, single submitter clinical testing This sequence change falls in the 5' UTR of the GJB1 gene. It does not change the encoded amino acid sequence of the GJB1 protein, but It falls at the last nucleotide of exon 1 of the GJB1 non-coding sequence. Frequency data for this variant from the ExAC database is not available, and its frequency in the general population is not known. This variant has been reported to segregate with CMT1X in three families (PMID: 21504505, 28283593). It has also been reported in multiple individuals affected with CMT1X (PMID: 22464564, 28283593, 26392352, 28768847, Invitae database). This variant is also known as c.-373G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 246014). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001249760 SCV001423793 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2020-03-11 criteria provided, single submitter clinical testing The GJB1 c.-17G>A variant occurs in the last base of the 5' untranslated region. This variant has been reported in at least four studies, in which it is found in a total of 26 individuals from eight unrelated families with Charcot-Marie-Tooth neuropathy X type 1 disorder (CMT1X) (Murphy et al. 2011; Arthur-Farraj et al. 2012; Antoniadi et al. 2015; Tomaselli et al. 2017). Affected individuals included both heterozygous females and hemizygous males, and this variant was shown to segregate with disease in five families (Murphy et al. 2011; Tomaselli et al. 2017). The c.-17G>A variant is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the c.-17G>A variant is classified as pathogenic for Charcot-Marie-Tooth neuropathy X type 1.
Athena Diagnostics Inc RCV000235476 SCV001476386 pathogenic not provided 2020-07-28 criteria provided, single submitter clinical testing Not found in the gnomAD genomes dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Splicing predictions are inconclusive. Nucleotide conservation is uninformative. Strong co-segregation with disease, and data includes affected and unaffected individuals from multiple families.

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