Submissions for variant NM_006019.4(TCIRG1):c.2008C>T (p.Arg670Ter)

gnomAD frequency: 0.00010  dbSNP: rs371263807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666300	SCV000790569	pathogenic	Autosomal recessive osteopetrosis 1	2017-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666300	SCV000807565	pathogenic	Autosomal recessive osteopetrosis 1	2017-09-01	criteria provided, single submitter	clinical testing	This nonsense variant has been previously reported as disease-causing and was found once in our laboratory with a missense variant (S474L, phase unknown) in a 17-year-old male with intellectual disability, autism spectrum, dysmorphisms, macrocephaly, advance bone age, precocious puberty, possible hearing loss, ichthyosis (and STS deletion), frequent fractures with decreased bone density, joint laxity.
Invitae	RCV000819121	SCV000959764	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg670*) in the TCIRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCIRG1 are known to be pathogenic (PMID: 10888887, 10942435, 11532986, 19448635). This variant is present in population databases (rs371263807, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with TCIRG1-related conditions (PMID: 11532986). ClinVar contains an entry for this variant (Variation ID: 551284). For these reasons, this variant has been classified as Pathogenic.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000666300	SCV001190573	pathogenic	Autosomal recessive osteopetrosis 1	2019-05-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000819121	SCV001249643	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199854	SCV001370586	pathogenic	Osteopetrosis	2020-05-29	criteria provided, single submitter	clinical testing	Variant summary: TCIRG1 c.2008C>T (p.Arg670X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.1e-05 in 184378 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TCIRG1 causing Osteopetrosis (7.1e-05 vs 0.0016), allowing no conclusion about variant significance. c.2008C>T has been reported in the literature in individuals affected with Osteopetrosis (Sobacchi_2001, Yang_2018, Yu_2014, Wang_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000819121	SCV003805505	pathogenic	not provided	2023-02-25	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24535484, 23721911, 31501239, 25525159, 32411386, 31589614, 31949009, 34545712, 11532986)
Natera, Inc.	RCV000666300	SCV001456354	pathogenic	Autosomal recessive osteopetrosis 1	2020-09-16	no assertion criteria provided	clinical testing