Submissions for variant NM_001077415.3(CRELD1):c.959del (p.Gln320fs)

gnomAD frequency: 0.00035  dbSNP: rs759473511

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000658951	SCV000780753	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	CRELD1: PVS1:Supporting
Undiagnosed Diseases Network, NIH	RCV001255986	SCV001432767	uncertain significance	CRELD1-related disorder	2020-02-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348769	SCV001543084	uncertain significance	Atrioventricular septal defect, susceptibility to, 2	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln320Argfs*25) in the CRELD1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CRELD1 cause disease. This variant is present in population databases (rs759473511, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 546928). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000658951	SCV001820429	likely pathogenic	not provided	2024-10-24	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 101 amino acids are replaced with 24 different amino acids; Reported in a patient with tetralogy of Fallot in published literature, although further clinical detail was not provided (PMID: 34328347); This variant is associated with the following publications: (PMID: 31589614, 32437232, 37947183, 34328347)
Revvity Omics, Revvity	RCV001348769	SCV003828629	uncertain significance	Atrioventricular septal defect, susceptibility to, 2	2021-11-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV003989115	SCV005440701	pathogenic	Jeffries-Lakhani neurodevelopmental syndrome	2024-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004972840	SCV005564877	pathogenic	Inborn genetic diseases	2024-11-04	criteria provided, single submitter	clinical testing	The c.959delA (p.Q320Rfs*25) alteration, located in coding exon 9 of the CRELD1 gene, consists of a deletion of one nucleotide at position 959, causing a translational frameshift with a predicted alternate stop codon after 25 amino acids. This alteration occurs at the 3' terminus of the CRELD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 24% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the - allele has an overall frequency of 0.03% (84/282702) total alleles studied. The highest observed frequency was 0.058% (75/129068) of European (non-Finnish) alleles. In a cohort of individuals with biallelic variants in CRELD1 presenting with early-onset neurodevelopmental disorder features and slowly progressive non-neurologic features, this was detected in compound heterozygous form in seven unrelated probands (Jeffries, 2023). Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV003989115	SCV004805653	pathogenic	Jeffries-Lakhani neurodevelopmental syndrome	2024-03-29	no assertion criteria provided	literature only