Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1PP5_ModerateBS2
The NM_001077415.3(CRELD1):c.523C>T(p.Arg175*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
CRELD1 (HGNC:14630): (cysteine rich with EGF like domains 1) This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]
PRRT3 (HGNC:26591): (proline rich transmembrane protein 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 3-9940912-C-T is Pathogenic according to our data. Variant chr3-9940912-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 465835.Status of the report is criteria_provided_single_submitter, 1 stars.
Atrioventricular septal defect, susceptibility to, 2 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Oct 01, 2024
This sequence change creates a premature translational stop signal (p.Arg175*) in the CRELD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRELD1 are known to be pathogenic (PMID: 37947183). This variant is present in population databases (rs774018674, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CRELD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 465835). For these reasons, this variant has been classified as Pathogenic. -