Variant 1-193142015-CAGAG-CAGAGAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024529.5(CDC73):c.687_688dupAG(p.Val230fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,348 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V230V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDC73
NM_024529.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.38

Variant links:

Genes affected

CDC73 (HGNC:16783): (cell division cycle 73) This gene encodes a tumor suppressor that is involved in transcriptional and post-transcriptional control pathways. The protein is a component of the the PAF protein complex, which associates with the RNA polymerase II subunit POLR2A and with a histone methyltransferase complex. This protein appears to facilitate the association of 3' mRNA processing factors with actively-transcribed chromatin. Mutations in this gene have been linked to hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, and parathyroid carcinoma. [provided by RefSeq, Jul 2009]

CDC73 links:

CDC73 (HGNC:):

CDC73 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-193142015-C-CAG is Pathogenic according to our data. Variant chr1-193142015-C-CAG is described in ClinVar as [Pathogenic]. Clinvar id is 241496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC73	NM_024529.5 linkuse as main transcript	c.687_688dupAG	p.Val230fs	frameshift_variant	7/17	ENST00000367435.5	NP_078805.3	Q6P1J9
CDC73	XM_006711537.5 linkuse as main transcript	c.687_688dupAG	p.Val230fs	frameshift_variant	7/11		XP_006711600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC73	ENST00000367435.5 linkuse as main transcript	c.687_688dupAG	p.Val230fs	frameshift_variant	7/17	1	NM_024529.5	ENSP00000356405.4		Q6P1J9

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251250

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74026

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	Frameshift 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; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 679insAG; This variant is associated with the following publications: (PMID: 19332451, 15606373, 14585940, 14715834, 25444225, 32590342, 31967039, 12434154) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 18, 2018	DNA sequence analysis of the CDC73 gene demonstrated a two base pair duplication, c.687_688dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 27 amino acids downstream of the mutation, p.Val230Glufs*28. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CDC73 protein with potentially abnormal function. This sequence change in CDC73 was previously found to segregate in families with hyperparathyroidism-jaw tumor syndrome [OMIM#145001] (Carpten et al. 2002; Simonds et al. 2004), a rare autosomal dominant disorder characterized by synchronous or metachronous occurrence of primary hyperparathyroidism, ossifying fibroma of the maxilla and/or mandible, renal tumor and uterine tumors. -

CDC73-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2023

The CDC73 c.687_688dupAG variant is predicted to result in a frameshift and premature protein termination (p.Val230Glufs*28). This variant was reported in individuals with hyperparathyroidism-jaw tumour syndrome (see, for example, Carpten et al. 2002. PubMed ID: 12434154, reported as 679insAG; Sirbiladze et al. 2019. PubMed ID: 31967039). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-193111145-C-CAG). Frameshift variants in CDC73 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Parathyroid carcinoma;C1704981:Hyperparathyroidism 2 with jaw tumors;C1840402:Hyperparathyroidism 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 12, 2021

- -

Parathyroid carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2023

This sequence change creates a premature translational stop signal (p.Val230Glufs*28) in the CDC73 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDC73 are known to be pathogenic (PMID: 12434154). This variant is present in population databases (rs763788378, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and/or isolated hyperparathyroidism (PMID: 12434154, 14715834, 25444225). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 241496). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2024

The c.687_688dupAG pathogenic mutation, located in coding exon 7 of the CDC73 gene, results from a duplication of AG at nucleotide position 687, causing a translational frameshift with a predicted alternate stop codon (p.V230Efs*28). This mutation has been reported in multiple families with both hyperparathyroidism–jaw tumor syndrome and also familial isolated primary hyperparathyroidism, and has been shown to segregate with disease in at least two families with multiple affected individuals (Carpten JD et al. Nat. Genet., 2002 Dec;32:676-80; Sirbiladze R et al. AACE Clin Case Rep Apr;5(3):e222-e225; Simonds W et al. J. Clin. Endocrinol. Metab. 2004 Jan;89(1):96-102). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over