X-2953163-C-G

Variant names:

• chrX-2953163-C-G
• rs80338711
• NM_000047.3:c.410G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 7P and 5B. PM5 PP3_Strong PP5 BS1_Supporting BS2

The NM_000047.3(ARSL):​c.410G>C​(p.Gly137Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000156 in 1,208,664 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 60 hem.)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 O:1
• Conservation: PhyloP100: 4.61
• Publications: 13 publications found

Genes affected

ARSL (HGNC:719): (arylsulfatase L) Arylsulfatase E is a member of the sulfatase family. It is glycosylated postranslationally and localized to the golgi apparatus. Sulfatases are essential for the correct composition of bone and cartilage matrix. X-linked chondrodysplasia punctata, a disease characterized by abnormalities in cartilage and bone development, has been linked to mutations in this gene. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the Y chromosome. [provided by RefSeq, Sep 2013]

ARSL Gene-Disease associations (from GenCC):

• X-linked chondrodysplasia punctata 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-2953163-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11525.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant X-2953163-C-G is Pathogenic according to our data. Variant chrX-2953163-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21033.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000178 (20/112469) while in subpopulation NFE AF = 0.000337 (18/53359). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3	c.410G>C	p.Gly137Ala	missense_variant	Exon 5 of 11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.410G>C	p.Gly137Ala	missense_variant	Exon 5 of 11	1	NM_000047.3	ENSP00000370526.3

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 20 AN: 112469 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000945

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000337

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 24 AN: 183389 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 168 AN: 1096195 Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 60 AN XY: 361667

African (AFR) AF: 0.00 AC: 0 AN: 26356

American (AMR) AF: 0.000114 AC: 4 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19314

East Asian (EAS) AF: 0.00 AC: 0 AN: 30114

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54082

European-Finnish (FIN) AF: 0.000124 AC: 5 AN: 40281

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4131

European-Non Finnish (NFE) AF: 0.000177 AC: 149 AN: 840806

Other (OTH) AF: 0.000174 AC: 8 AN: 45969

GnomAD4 genome AF: 0.000178 AC: 20 AN: 112469 Hom.: 0 Cov.: 24 AF XY: 0.000173 AC XY: 6 AN XY: 34625

African (AFR) AF: 0.00 AC: 0 AN: 30943

American (AMR) AF: 0.0000945 AC: 1 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3610

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.000162 AC: 1 AN: 6160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000337 AC: 18 AN: 53359

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked chondrodysplasia punctata 1 Pathogenic:1 Uncertain:1 Other:1

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

Nov 18, 2024

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PP3 supporting -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Chondrodysplasia punctata, brachytelephalangic, autosomal Pathogenic:1 Uncertain:1

Sep 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Coffin-Siris syndrome 1 Pathogenic:1

Mar 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:1

Aug 06, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

not specified Uncertain:1

Aug 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

ARSL-related disorder Uncertain:1

Jan 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.75
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	.;.;H;.
PhyloP100		4.6
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.92
MVP		0.96
MPC		1.3
ClinPred		0.94	D
GERP RS		3.5
Varity_R		0.81
gMVP		0.99
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338711; hg19: chrX-2871204;