Submissions for variant NM_019032.6(ADAMTSL4):c.2270del (p.Gly757fs)

dbSNP: rs747160538

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV001785892	SCV002021309	likely pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001785892	SCV003293011	pathogenic	not provided	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly757Valfs*62) in the ADAMTSL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADAMTSL4 are known to be pathogenic (PMID: 20564469, 28642162). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADAMTSL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1323859). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV003339742	SCV004049596	likely pathogenic	Ectopia lentis et pupillae	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003339741	SCV004049597	likely pathogenic	Ectopia lentis 2, isolated, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594589	SCV005086349	pathogenic	Craniosynostosis with ectopia lentis	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ectopia lentis et pupillae (MIM#225200), isolated ectopia lentis (MIM#225100) and craniosynostosis with ectopia lentis (MONDO:0011347; PMID: 35378950). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotype may vary significantly among patients, even within the same family (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been regarded as likely pathogenic by a clinical laboratory in ClinVar and reported in three siblings with ectopia lentis et pupillae (PMID: 36089008). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001785892	SCV005326027	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	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 (gnomAD); This variant is associated with the following publications: (PMID: 36089008)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003339741	SCV005374095	pathogenic	Ectopia lentis 2, isolated, autosomal recessive	2024-09-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005040376	SCV005665869	pathogenic	Ectopia lentis et pupillae; Ectopia lentis 2, isolated, autosomal recessive	2024-05-15	criteria provided, single submitter	clinical testing