rs397515874

Variant names:

• chrX-101398857-C-G
• rs397515874
• NM_000169.3:c.729G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-101398857-C-G
• chrX-101398857-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000169.3(GLA):​c.729G>C​(p.Leu243Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L243W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.655
• Publications: 14 publications found

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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 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-101398858-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4087485.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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant X-101398857-C-G is Pathogenic according to our data. Variant chrX-101398857-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42462.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.729G>C	p.Leu243Phe	missense_variant	Exon 5 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.729G>C	p.Leu243Phe	missense_variant	Exon 5 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+3400C>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Leu243Phe v ariant has been reported in one individual with classic Fabry disease, though no control studies were performed (Germain 2002). In addition, a different change at the same position (Leu243Trp) with good evidence for pathogenicity has been i dentified in an individual with Fabry disease as well as several affected family members (Rozenfeld 2006). These findings support a pathogenic role for the Leu2 43Phe variant as do the clinical features reported for an individual tested by o ur laboratory (HCM and focal and segmental glomerulosclerosis are consistent wit h Fabry disease (Fogo 2010). However, leucine (Leu) at position 243 is not 100% conserved in evolution (frog has a methionine and mosquito has a threonine), rai sing the possibility that a change would be tolerated. In summary, additional da ta is needed to determine significance of the Leu243Phe variant with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostCm	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
PhyloP100		0.66
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.81		Loss of catalytic residue at L243 (P = 0.0111);.;
MVP		1.0
MPC		1.8
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.79
gMVP		0.97
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs397515874; hg19: chrX-100653845;