NM_000169.3(GLA):c.124A>C (p.Met42Leu) AND Fabry disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 17, 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:: RCV000809963.14

Allele description [Variation Report for NM_000169.3(GLA):c.124A>C (p.Met42Leu)]

NM_000169.3(GLA):c.124A>C (p.Met42Leu)

Genes:

RPL36A-HNRNPH2:RPL36A-HNRNPH2 readthrough [Gene - HGNC]
GLA:galactosidase alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_000169.3(GLA):c.124A>C (p.Met42Leu)

HGVS:

NC_000023.11:g.101407780T>G
NG_007119.1:g.5184A>C
NG_016327.1:g.4578T>G
NM_000169.3:c.124A>CMANE SELECT
NM_001199973.2:c.301-4156T>G
NM_001199974.2:c.178-4156T>G
NM_001406747.1:c.124A>C
NM_001406748.1:c.124A>C
NM_001406749.1:c.124A>C
NP_000160.1:p.Met42Leu
NP_000160.1:p.Met42Leu
NP_001393676.1:p.Met42Leu
NP_001393677.1:p.Met42Leu
NP_001393678.1:p.Met42Leu
LRG_672t1:c.124A>C
LRG_672:g.5184A>C
LRG_672p1:p.Met42Leu
NC_000023.10:g.100662768T>G
NM_000169.2:c.124A>C
NR_164783.1:n.146A>C
NR_176252.1:n.146A>C
NR_176253.1:n.146A>C
P06280:p.Met42Leu

Protein change:

M42L

Links:

UniProtKB: P06280#VAR_062551; dbSNP: rs797044613

NCBI 1000 Genomes Browser:

rs797044613

Molecular consequence:

NM_001199973.2:c.301-4156T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.178-4156T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.124A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.124A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.124A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406749.1:c.124A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.146A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.146A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.146A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Fabry disease
Synonyms:: Angiokeratoma, diffuse; Anderson-Fabry disease; Hereditary dystopic lipidosis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000950149	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15492942, 15712228, 27657681, 8875188, 12175777, 18205205, 23935525, 26415523, 27560961, 28492532 http//dx.doi.org/10.16966/2380-5498.124,
SCV001427212	Clinical Genomics Laboratory, Stanford Medicine	no assertion criteria provided	Pathogenic (Dec 18, 2019)	germline	clinical testing
SCV002054825	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000950149

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

http//dx.doi.org/10.16966/2380-5498.124,

SCV001427212

Clinical Genomics Laboratory, Stanford Medicine

no assertion criteria provided

Pathogenic
(Dec 18, 2019)

germline

clinical testing

SCV002054825

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 15, 2021)

germline

clinical testing

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

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	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel alpha-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease.

Rosenthal D, Lien YH, Lager D, Lai LW, Shang S, Leung N, Fervenza FC.

Am J Kidney Dis. 2004 Nov;44(5):e85-9.

PubMed [citation]

PMID:: 15492942

Detection of alpha-galactosidase a mutations causing Fabry disease by denaturing high performance liquid chromatography.

Shabbeer J, Robinson M, Desnick RJ.

Hum Mutat. 2005 Mar;25(3):299-305.

PubMed [citation]

PMID:: 15712228

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000950149.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 42 of the GLA protein (p.Met42Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 15492942, 15712228; http//dx.doi.org/10.16966/2380-5498.124). ClinVar contains an entry for this variant (Variation ID: 193056). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 27657681). This variant disrupts the p.Met42 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875188, 12175777, 18205205, 23935525, 26415523, 27560961). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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 Clinical Genomics Laboratory, Stanford Medicine, SCV001427212.1

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

Description

The p.Met42Leu variant in the GLA gene has been previously reported in two unrelated males with Fabry disease (Rosenthal et al., 2004; Shabbeer, Robinson & Desnick, 2005). Alpha-galactosidase A enzyme activity was tested and reported low in one of the published individuals. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Wellestablished in vitro functional studies of p.Met42Leu variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Benjamin et al., 2017; Oommen et al., 2019). Additionally, multiple different amino acid changes, p.Met42Ile, p.Met42Thr, and p.Met42Val, have been previously reported as disease-causing at this residue, which suggests another change at this residue, such as p.Met42Leu, may similarly disrupt protein function. The p.Met42Leu variant is located in a region where other pathogenic and likely pathogenic variants have been described without benign variation. Pathogenic and likely pathogenic variants have been described in this region and disrupt the function of GLA, resulting in reduced or absent alpha-galactosidase A enzyme activity. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Met42Leu variant as pathogenic for X-linked Fabry disease based on the information above. [ACMG evidence codes used: PS3; PM1; PM2; PM5; PP4]

#	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 Genome-Nilou Lab, SCV002054825.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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