Submissions for variant NM_000067.3(CA2):c.681del (p.Lys227fs)

dbSNP: rs779869368

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779564	SCV000916238	likely pathogenic	Osteopetrosis with renal tubular acidosis	2017-04-28	criteria provided, single submitter	clinical testing	The CA2 c.681delA (p.Lys227AsnfsTer13) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Lys227AsnfsTer13 variant has been reported in one study and is found in a homozygous state in seven unrelated individuals diagnosed with osteopetrosis with renal tubular acidosis (Hu et al. 1994). Control data are unavailable for this variant and it is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium but this is based on one allele only in a region of good sequencing coverage so the variant is presumed to be rare. The p.Lys227AsnfsTer13 variant when expressed in COS cells produced an enzymatically inactive protein that was expressed at much lower levels than wild type protein (Hu et al. 1994). Based on the evidence and the potential impact of frameshift variants, the p.Lys227AsnfsTer13 variant is classified as likely pathogenic for osteopetrosis with renal tubular acidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000779564	SCV001752445	pathogenic	Osteopetrosis with renal tubular acidosis	2021-06-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873184	SCV002205939	pathogenic	not provided	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys227Asnfs*13) in the CA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the CA2 protein. This variant is present in population databases (rs779869368, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with CA2 deficiency (PMID: 8128957). This variant is also known as a frameshift at amino acid 227, resulting in incorporation of 12 abnormal amino acids before termination at a TGA codon. ClinVar contains an entry for this variant (Variation ID: 632527). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CA2 function (PMID: 8128957). This variant disrupts a region of the CA2 protein in which other variant(s) (p.Glu233Glyfs*2) have been observed in individuals with CA2-related conditions (PMID: 15300855). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001873184	SCV003925048	pathogenic	not provided	2023-05-14	criteria provided, single submitter	clinical testing	In vitro published functional studies demonstrate the variant results in an inactive, insoluble, and quickly degraded enzyme (Hu et al., 1994); Frameshift variant predicted to result in protein truncation, as the last 34 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27535533, 8128957, 24077912)