NM_000308.4(CTSA):c.146A>G (p.Gln49Arg) AND Combined deficiency of sialidase AND beta galactosidase

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000000408.9

Allele description [Variation Report for NM_000308.4(CTSA):c.146A>G (p.Gln49Arg)]

NM_000308.4(CTSA):c.146A>G (p.Gln49Arg)

Gene:

CTSA:cathepsin A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_000308.4(CTSA):c.146A>G (p.Gln49Arg)

HGVS:

NC_000020.11:g.45891714A>G
NG_008291.1:g.5763A>G
NG_033108.1:g.4574T>C
NM_000308.4:c.146A>GMANE SELECT
NM_001127695.3:c.146A>G
NM_001167594.3:c.146A>G
NP_000299.3:p.Gln49Arg
NP_001121167.1:p.Gln49Arg
NP_001161066.2:p.Gln49Arg
NC_000020.10:g.44520353A>G
NM_000308.4:c.146A>G
NR_133656.2:n.191A>G

Protein change:

Q49R; GLN49ARG

Links:

OMIM: 613111.0003; dbSNP: rs137854541

NCBI 1000 Genomes Browser:

rs137854541

Molecular consequence:

NM_000308.4:c.146A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127695.3:c.146A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167594.3:c.146A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_133656.2:n.191A>G - 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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Taxonomy Links for Protein (Select 722491015) (1)
Taxonomy
Vestiaria coccinea mitochondrion, complete genome
Vestiaria coccinea mitochondrion, complete genome
gi|722491005|ref|NC_025620.1||gnl|N ENOMES|39624

Nucleotide
rpsR [Bacillus subtilis subsp. subtilis str. 168]
rpsR [Bacillus subtilis subsp. subtilis str. 168]
Gene ID:937906

Gene
cytochrome c oxidase subunit III (mitochondrion) [Drepanis coccinea]
cytochrome c oxidase subunit III (mitochondrion) [Drepanis coccinea]
gi|722491012|ref|YP_009107959.1|

Protein
NADH dehydrogenase subunit 5 (mitochondrion) [Drepanis coccinea]
NADH dehydrogenase subunit 5 (mitochondrion) [Drepanis coccinea]
gi|722491006|ref|YP_009107963.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020552	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004028593	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26259553, 18396002, 8514852 Citation Link,
SCV004298091	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18396002, 26259553, 8514852, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020552

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 1993)

germline

literature only

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

SCV004028593

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 25, 2023)

germline

clinical testing

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

Citation Link,

SCV004298091

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 11, 2024)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A case of galactosialidosis with a homozygous Q49R point mutation.

Matsumoto N, Gondo K, Kukita J, Higaki K, Paragison RC, Nanba E.

Brain Dev. 2008 Oct;30(9):595-8. doi: 10.1016/j.braindev.2008.01.012. Epub 2008 Apr 18.

PubMed [citation]

PMID:: 18396002

Chemical chaperone treatment for galactosialidosis: Effect of NOEV on β-galactosidase activities in fibroblasts.

Hossain MA, Higaki K, Shinpo M, Nanba E, Suzuki Y, Ozono K, Sakai N.

Brain Dev. 2016 Feb;38(2):175-80. doi: 10.1016/j.braindev.2015.07.006. Epub 2015 Aug 7.

PubMed [citation]

PMID:: 26259553

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000020552.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a Japanese child with galactosialidosis (GSL; 256540), Shimmoto et al. (1993) identified an A-to-G transition in exon 2 of the CTSA gene, resulting in a gln49-to-arg (Q49R) substitution. This mutation, like the W65R (613111.0004), S90L (613111.0005), and Y249N (613111.0007) mutations, was found in compound heterozygosity with the common intron 7 splice site mutation (613111.0002).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004028593.1

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

Description

Variant summary: CTSA c.146A>G (p.Gln49Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249136 control chromosomes (gnomAD). c.146A>G has been reported in the literature in individuals affected with Galactosialidosis (Shimmoto_1993, Hossain_2016, Matsumoto_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that cells with the variant protein lacked carboxypeptidase, alpha-neuraminidase, and beta-galactosidase activity (Shimmoto_1993). The following publications have been ascertained in the context of this evaluation (PMID: 8514852, 26259553, 18396002). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as 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, SCV004298091.1

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

Description

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 67 of the CTSA protein (p.Gln67Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with galactosialidosis (PMID: 8514852, 18396002, 26259553). This variant is also known as Q49R. ClinVar contains an entry for this variant (Variation ID: 377). 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 CTSA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTSA function (PMID: 8514852). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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

Last Updated: Sep 29, 2024

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