rs786204748

Variant names:

• chr22-50625443-GTGGTATCAC-G
• rs765905826
• NM_000487.6:c.1223_1231delGTGATACCA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_000487.6(ARSA):​c.1223_1231delGTGATACCA​(p.Ser408_Thr410del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000276 in 1,447,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ARSA NM_000487.6 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.29
• Publications: 2 publications found

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ARSA Gene-Disease associations (from GenCC):

• metachromatic leukodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• metachromatic leukodystrophy, juvenile form

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000487.6.
• PP5: Variant 22-50625443-GTGGTATCAC-G is Pathogenic according to our data. Variant chr22-50625443-GTGGTATCAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 189170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 8 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 8 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000837 AC: 2 AN: 238866 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000935

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447764 Hom.: 0 AF XY: 0.00000418 AC XY: 3 AN XY: 718444

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.0000226 AC: 1 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 84778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103598

Other (OTH) AF: 0.00 AC: 0 AN: 59814

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:4

Dec 11, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARSA c.1223_1231delGTGATACCA (p.Ser408_Thr410del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 8.4e-06 in 238866 control chromosomes. c.1223_1231delGTGATACCA has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Regis_1998, Biffi_2008, Cesani_2015, Rafi_2003, Galla_2013). These data indicate that the variant is very likely to be associated with disease. The variant results in significantly reduced enzyme activity (Regis_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 02, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1223_1231del, results in the deletion of 3 amino acid(s) of the ARSA protein (p.Ser408_Thr410del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765905826, gnomAD 0.003%). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9490297, 12809637, 18786133, 22993277, 23559313). This variant is also known as c.1215_1223del, c.1216-24del9, c.1216del9, c.1217_1225del, and 2320del9. ClinVar contains an entry for this variant (Variation ID: 189170). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARSA: PM3:Very Strong, PM2, PM4, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs765905826; hg19: chr22-51063871;