Submissions for variant NM_000047.3(ARSL):c.410G>C (p.Gly137Ala)

gnomAD frequency: 0.00009  dbSNP: rs80338711

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169650	SCV000221173	uncertain significance	not specified	2013-08-08	criteria provided, single submitter	clinical testing	The Gly137Ala variant in ARSE has been previously identified in 2 males with chondrodysplasia punctata; however, this variant was also identified in one unaffected male family member (Sheffield 1998, Nino 2008). Variants in a paralogous gene (ARSB) at the same position have also been identified in an individual with Maroteux-Lamy syndrome, which also features skeletal abnormalities (Franco 1995). Functional studies indicate that the Gly137Ala variant leads to reduced ARSE activity (Matos-Miranda 2013). In summary, although some data support a disease-causing role, there is currently insufficient evidence for pathogenicity leading to a current classification of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228045	SCV001483508	uncertain significance	Chondrodysplasia punctata, brachytelephalangic, autosomal	2022-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 137 of the ARSE protein (p.Gly137Ala). This variant is present in population databases (rs80338711, gnomAD 0.02%). This missense change has been observed in individuals with X-linked chondrodysplasia punctata (PMID: 9863597, 18348268). ClinVar contains an entry for this variant (Variation ID: 21033). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ARSE function (PMID: 23470839). This variant disrupts the p.Gly137 amino acid residue in ARSE. Other variant(s) that disrupt this residue have been observed in individuals with ARSE-related conditions (PMID: 7720070), which suggests that this may be a clinically significant amino acid residue. 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	RCV001547250	SCV001766908	likely pathogenic	not provided	2025-01-17	criteria provided, single submitter	clinical testing	Identified in unrelated male patients with clinical features of chondrodysplasia punctata; however, in one family, the variant was also identified in a clinically unaffected mother and maternal grandfather, suggesting possible reduced penetrance of this variant (PMID: 18348268, 9863597); Published functional studies demonstrate reduced ARSL activity (PMID: 23470839); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7720070, 24645908, 24033266, 28654958, 34426522, 9863597, 34697415, 29565423, 20301713, 23470839, 18348268)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020092	SCV002768603	likely pathogenic	X-linked chondrodysplasia punctata 1	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine (exon 5). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 10 hemizygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 hemizygotes, 0 homozygotes). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative missense change at the same residue (p.Gly137Val) has been reported as pathogenic and was found in patients with chondrodysplasia punctata (ClinVar, PMID: 7720070). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic in three hemizygous patients with chondrodysplasia punctata (ClinVar, PMID: 23470839, PMID: 18348268, PMID: 9863597). The variant was confirmed to be inherited from asymptomatic, heterozygous mothers in all three cases. This variant has also been described as a VUS, in a primary care cohort of unknown phenotype (PMID: 29565423). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional analysis of transfected COS-7 cells found mutant protein had negligible enzyme activity (PMID: 23470839) (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228045	SCV005040643	likely pathogenic	Chondrodysplasia punctata, brachytelephalangic, autosomal	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: ARSL c.410G>C (p.Gly137Ala) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of 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 0.00013 in 205545 control chromosomes (gnomAD). c.410G>C has been reported in the literature in individuals affected with Chondrodysplasia Punctata 1, X-Linked Recessive (Sheffield_1998, Nino_2008). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Matos-Miranda_2013). The most pronounced variant effect results in 10%-<30% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 9863597, 18348268, 23470839, 34697415). ClinVar contains an entry for this variant (Variation ID: 21033). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004541010	SCV005040817	likely pathogenic	Coffin-Siris syndrome 1	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: ARID1B c.410G>C (p.Gly137Ala) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 137314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.410G>C in individuals affected with Coffin-Siris Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneReviews	RCV000020092	SCV000040400	not provided	X-linked chondrodysplasia punctata 1		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003944832	SCV004763350	uncertain significance	ARSL-related disorder	2024-01-15	no assertion criteria provided	clinical testing	The ARSL c.410G>C variant is predicted to result in the amino acid substitution p.Gly137Ala. This variant has been previously reported in individuals with mild or a suspected diagnosis of chondrodysplasia punctata (Sheffield et al. 1998. PubMed ID: 9863597; Nino et al. 2008. PubMed ID: 18348268). In one study the variant was also found in proband's asymptomatic maternal grandfather and his carrier mother (Sheffield et al. 1998. PubMed ID: 9863597), which can be suggestive of reduced penetrance. In vitro functional studies found that over a specific time course this variant had negligible activity compared to wild type allele (Matos-Miranda et al. 2013. PubMed ID: 23470839). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including ten hemizygous alleles. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.