Submissions for variant NM_024529.5(CDC73):c.131+1G>A

dbSNP: rs587776558

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413007	SCV000490457	pathogenic	not provided	2018-04-12	criteria provided, single submitter	clinical testing	The c.131+1G>A splice site variant in the CDC73 gene has been previously reported in association with multiple families with hyperparathyroidism and parathyroid tumors (Cetani et al., 2004; Bradley et al., 2005). Functional studies show c.131+1G>A results in loss of 30 nucleotides from exon 1 of the CDC73 gene (Bradley et al., 2005). Based on currently available evidence, we consider c.131+1G>A to be pathogenic, and its presence consistent with a diagnosis of a CDC73-related disorder
Invitae	RCV001054064	SCV001218357	pathogenic	Parathyroid carcinoma	2023-01-16	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: 3276). This variant is also known as IVS1+1G>A. Disruption of this splice site has been observed in individual(s) with familial isolated primary hyperparathyroidism (PMID: 15531515, 16061557). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the CDC73 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 CDC73 are known to be pathogenic (PMID: 12434154).
Ambry Genetics	RCV002381237	SCV002694321	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-16	criteria provided, single submitter	clinical testing	The c.131+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the CDC73 gene. This variant has been detected in multiple individuals with primary hyperparathyroidism and reported to result in partial skipping of exon 1 (Cetani F et al. J Clin Endocrinol Metab, 2004 Nov;89:5583-91; Bradley KJ et al. J Med Genet, 2005 Aug;42:e51; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496245	SCV002809719	pathogenic	Hyperparathyroidism 1; Parathyroid carcinoma; Hyperparathyroidism 2 with jaw tumors	2021-07-06	criteria provided, single submitter	clinical testing
OMIM	RCV000003435	SCV000023593	pathogenic	Hyperparathyroidism 1	2004-11-01	no assertion criteria provided	literature only
OMIM	RCV000003436	SCV000023594	pathogenic	Parathyroid adenoma, somatic	2004-11-01	no assertion criteria provided	literature only
GeneReviews	RCV001054064	SCV002574701	not provided	Parathyroid carcinoma		no assertion provided	literature only