Submissions for variant NM_019032.6(ADAMTSL4):c.2236C>T (p.Arg746Cys)

gnomAD frequency: 0.00006  dbSNP: rs751676813

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001099079	SCV001255498	uncertain significance	Ectopia lentis 2, isolated, autosomal recessive	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873482	SCV002187364	pathogenic	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 746 of the ADAMTSL4 protein (p.Arg746Cys). This variant is present in population databases (rs751676813, gnomAD 0.01%). This missense change has been observed in individual(s) with ectopia lentis (PMID: 36208099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 875326). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADAMTSL4 protein function. This variant disrupts the p.Arg746 amino acid residue in ADAMTSL4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25975359, 28394649; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV003339488	SCV004049589	uncertain significance	Ectopia lentis et pupillae	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001099079	SCV004049590	uncertain significance	Ectopia lentis 2, isolated, autosomal recessive	2023-04-11	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001099079	SCV004806217	uncertain significance	Ectopia lentis 2, isolated, autosomal recessive	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768860	SCV005381139	likely pathogenic	ADAMTSL4-related disorder	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: ADAMTSL4 c.2236C>T (p.Arg746Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 244482 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ADAMTSL4 causing ADAMTSL4-Related Disorders, allowing no conclusion about variant significance. c.2236C>T has been reported in the literature in individuals affected with Ectopia lentis (Lenassi_2020, Guo_2023, Musleh_2023). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been determined to be pathogenic by our lab (c.2237G>A, p.Arg746His), supporting the critical relevance of codon 746 to ADAMTSL4 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35042684, 37107549, 31848469). ClinVar contains an entry for this variant (Variation ID: 875326). Based on the evidence outlined above, the variant was classified as likely pathogenic.