ClinVar Miner

Submissions for variant NM_006019.4(TCIRG1):c.1554+2T>A

gnomAD frequency: 0.00003  dbSNP: rs761918801
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001057306 SCV001221792 pathogenic not provided 2023-05-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as 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: 852649). This variant is also known as T9000A (exon 13, +2 donor splice site). Disruption of this splice site has been observed in individuals with autosomal recessive osteopetrosis (PMID: 11532986, 20424301). This variant is present in population databases (rs761918801, gnomAD 0.02%). This sequence change affects a donor splice site in intron 13 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).
Revvity Omics, Revvity RCV001784608 SCV002018945 pathogenic Autosomal recessive osteopetrosis 1 2020-11-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155348 SCV003844427 pathogenic Osteopetrosis 2023-02-07 criteria provided, single submitter clinical testing Variant summary: TCIRG1 c.1554+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 250308 control chromosomes. c.1554+2T>A has been reported in the literature in multiple individuals affected with Osteopetrosis (Sobacchi_2001, Phadke_2010, Liu_2021). This inclides at least one individual reported as compound heterozygous with another likely pathogenic truncating variant, and a family showing evidence of cosegregation of the variant with Osteopetrosis. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001784608 SCV004205807 pathogenic Autosomal recessive osteopetrosis 1 2022-11-14 criteria provided, single submitter clinical testing

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