chrX-101400689-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000169.3(GLA):c.616C>G(p.Leu206Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,175,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L206F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.492

Publications

2 publications found

Variant links:

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

GLA links:

RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

RPL36A-HNRNPH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 28 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000169.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-101400688-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4087437.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.616C>G	p.Leu206Val	missense_variant	Exon 4 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.616C>G	p.Leu206Val	missense_variant	Exon 4 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+5232G>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.40e-7

AC:

AN:

1063893

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

336197

show subpopulations

African (AFR)

AF:

0.0000388

AC:

AN:

25770

American (AMR)

AF:

0.00

AC:

AN:

35139

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19145

East Asian (EAS)

AF:

0.00

AC:

AN:

30067

South Asian (SAS)

AF:

0.00

AC:

AN:

53184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4058

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

811034

Other (OTH)

AF:

0.00

AC:

AN:

45020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33878

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30694

American (AMR)

AF:

0.00

AC:

AN:

10491

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6023

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53173

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 18, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29121657) -

Fabry disease

Uncertain:1

Oct 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 206 of the GLA protein (p.Leu206Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 180839). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L206V variant (also known as c.616C>G), located in coding exon 4 of the GLA gene, results from a C to G substitution at nucleotide position 616. The leucine at codon 206 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort; however, clinical details were not provided (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Benign

0.069

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Uncertain

0.58

D;.

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

1.7

L;.

PhyloP100

0.49

PrimateAI

Benign

0.35

PROVEAN

Benign

0.040

N;.

REVEL

Uncertain

0.59

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.84

P;.

Vest4

0.32

MutPred

0.47

Gain of sheet (P = 0.0344);.;

MVP

0.98

MPC

1.1

ClinPred

0.16

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.95

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over