NM_000046.5(ARSB):c.215T>C (p.Leu72Pro) AND Mucopolysaccharidosis type 6

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 15, 2021
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000677515.6

Allele description [Variation Report for NM_000046.5(ARSB):c.215T>C (p.Leu72Pro)]

NM_000046.5(ARSB):c.215T>C (p.Leu72Pro)

Genes:

LOC129994126:ATAC-STARR-seq lymphoblastoid silent region 16127 [Gene]
ARSB:arylsulfatase B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q14.1

Genomic location:

Preferred name:

NM_000046.5(ARSB):c.215T>C (p.Leu72Pro)

HGVS:

NC_000005.10:g.78985034A>G
NG_007089.1:g.6501T>C
NM_000046.5:c.215T>CMANE SELECT
NM_198709.3:c.215T>C
NP_000037.2:p.Leu72Pro
NP_942002.1:p.Leu72Pro
NC_000005.9:g.78280857A>G
NM_000046.4:c.215T>C

Protein change:

L72P

Links:

dbSNP: rs397514441

NCBI 1000 Genomes Browser:

rs397514441

Molecular consequence:

NM_000046.5:c.215T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198709.3:c.215T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis type 6 (MPS6)
Synonyms:: MPS VI; Mucopolysaccharidosis type VI; MPS 6; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009661; MedGen: C0026709; Orphanet: 583; OMIM: 253200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000803025	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2018)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 24373060, 25741868, 30118150
SCV002132557	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24373060, 16435196, 17458871, 25190157, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000803025

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 1, 2018)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

SCV002132557

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 15, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in the ARSB gene.

Tomanin R, Karageorgos L, Zanetti A, Al-Sayed M, Bailey M, Miller N, Sakuraba H, Hopwood JJ.

Hum Mutat. 2018 Dec;39(12):1788-1802. doi: 10.1002/humu.23613. Epub 2018 Sep 17. Review.

PubMed [citation]

PMID:: 30118150
PMCID:: PMC6282714

See all PubMed Citations (7)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV000803025.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

Very low frequency in GnomAD (PM2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002132557.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

ClinVar contains an entry for this variant (Variation ID: 559739). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 24373060). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 72 of the ARSB protein (p.Leu72Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu72 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16435196, 17458871, 25190157; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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