NM_000308.4(CTSA):c.112del (p.Leu38fs) AND Combined deficiency of sialidase AND beta galactosidase

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Apr 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001260321.8

Allele description [Variation Report for NM_000308.4(CTSA):c.112del (p.Leu38fs)]

NM_000308.4(CTSA):c.112del (p.Leu38fs)

Gene:

CTSA:cathepsin A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_000308.4(CTSA):c.112del (p.Leu38fs)

HGVS:

NC_000020.11:g.45891680del
NG_008291.1:g.5729del
NG_033108.1:g.4609del
NM_000308.4:c.112delMANE SELECT
NM_001127695.3:c.112del
NM_001167594.3:c.112del
NP_000299.3:p.Leu38fs
NP_001121167.1:p.Leu38fs
NP_001161066.2:p.Leu38fs
NC_000020.10:g.44520318del
NC_000020.10:g.44520319del
NM_000308.3:c.166delC
NM_000308.4:c.112delCMANE SELECT
NR_133656.2:n.157del

Protein change:

L38fs

Links:

dbSNP: rs1241378191

NCBI 1000 Genomes Browser:

rs1241378191

Molecular consequence:

NM_000308.4:c.112del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001127695.3:c.112del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001167594.3:c.112del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_133656.2:n.157del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Combined deficiency of sialidase AND beta galactosidase (GSL)
Synonyms:: CATHEPSIN A DEFICIENCY; Galactosialidosis; Goldberg syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009737; MedGen: C0268233; Orphanet: 351; OMIM: 256540

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001437246	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003443780	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8968752, 15110321, 23915561, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001437246

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 6, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV003443780

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2022)

germline

clinical testing

PubMed (4)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis.

Zhou XY, van der Spoel A, Rottier R, Hale G, Willemsen R, Berry GT, Strisciuglio P, Morrone A, Zammarchi E, Andria G, d'Azzo A.

Hum Mol Genet. 1996 Dec;5(12):1977-87. Erratum in: Hum Mol Genet 1997 Jan;6(1):146.

PubMed [citation]

PMID:: 8968752

New mutations in the PPBG gene lead to loss of PPCA protein which affects the level of the beta-galactosidase/neuraminidase complex and the EBP-receptor.

Malvagia S, Morrone A, Caciotti A, Bardelli T, d'Azzo A, Ancora G, Zammarchi E, Donati MA.

Mol Genet Metab. 2004 May;82(1):48-55.

PubMed [citation]

PMID:: 15110321

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001437246.3

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

Description

Variant summary: CTSA c.112delC/p.Leu38SerfsX54 (also known as delC118) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 247276 control chromosomes (gnomAD). c.112delC has been reported in literature at least in one compound heterozygous individual affected with Galactosialidosis (Zhou_1996). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443780.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 981068). This variant is also known as ŒîC118. This premature translational stop signal has been observed in individual(s) with galactosialidosis (PMID: 8968752). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Leu56Serfs*54) in the CTSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTSA are known to be pathogenic (PMID: 15110321, 23915561).

#	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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