ClinVar Miner

Submissions for variant NM_006019.4(TCIRG1):c.117+1G>A

gnomAD frequency: 0.00002  dbSNP: rs377303800
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667120 SCV000791520 likely pathogenic Autosomal recessive osteopetrosis 1 2017-05-16 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000667120 SCV000915549 uncertain significance Autosomal recessive osteopetrosis 1 2018-10-23 criteria provided, single submitter clinical testing The TCIRG1 c.117+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The variant is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database, though this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. Due to the potential impact of splice site (donor) variants and the lack of clarifying evidence, the c.117+1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for osteopetrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000799615 SCV000939286 likely pathogenic not provided 2023-07-26 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 551945). Disruption of this splice site has been observed in individual(s) with autosomal recessive infantile osteopetrosis (PMID: 11532986). This variant is present in population databases (rs377303800, gnomAD 0.007%). This sequence change affects a donor splice site in intron 2 of the TCIRG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TCIRG1 are known to be pathogenic (PMID: 10888887, 10942435, 11532986, 19448635).
3billion RCV000667120 SCV002521714 pathogenic Autosomal recessive osteopetrosis 1 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with TCIRG1 related disorder (ClinVar ID: VCV000551945). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV000667120 SCV004205738 pathogenic Autosomal recessive osteopetrosis 1 2023-09-30 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000667120 SCV004238378 pathogenic Autosomal recessive osteopetrosis 1 2023-06-27 criteria provided, single submitter clinical testing

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