NM_000169.3(GLA):c.945C>T (p.Asp315=) AND not specified

Germline classification:: Benign/Likely benign (4 submissions)
Last evaluated:: Nov 16, 2017
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:: RCV000035315.15

Allele description [Variation Report for NM_000169.3(GLA):c.945C>T (p.Asp315=)]

NM_000169.3(GLA):c.945C>T (p.Asp315=)

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.945C>T (p.Asp315=)

Other names:

p.D315D:GAC>GAT

HGVS:

NC_000023.11:g.101398424G>A
NG_007119.1:g.14540C>T
NM_000169.3:c.945C>TMANE SELECT
NM_001199973.2:c.300+2967G>A
NM_001199974.2:c.177+6602G>A
NM_001406747.1:c.1068C>T
NM_001406748.1:c.945C>T
NP_000160.1:p.Asp315=
NP_000160.1:p.Asp315=
NP_001393676.1:p.Asp356=
NP_001393677.1:p.Asp315=
LRG_672t1:c.945C>T
LRG_672:g.14540C>T
LRG_672p1:p.Asp315=
NC_000023.10:g.100653412G>A
NM_000169.2(GLA):c.945C>T
NM_000169.2:c.945C>T
NR_164783.1:n.1024C>T
NR_176252.1:n.875C>T
NR_176253.1:n.1082C>T
c.945C>T
p.Asp315=
p.Asp315Asp
p.D315D

Links:

dbSNP: rs151208856

NCBI 1000 Genomes Browser:

rs151208856

Molecular consequence:

NM_001199973.2:c.300+2967G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6602G>A - intron variant - [Sequence Ontology: SO:0001627]
NR_164783.1:n.1024C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.875C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.1082C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000169.3:c.945C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001406747.1:c.1068C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001406748.1:c.945C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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cytchrome oxidase subunit I, partial (mitochondrion) [Uliodon sp. CG182]
cytchrome oxidase subunit I, partial (mitochondrion) [Uliodon sp. CG182]
gi|1148359093|gb|AQS17655.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058963	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Jun 17, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000207804	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Dec 11, 2012)	germline	clinical testing	Citation Link,
SCV000919434	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Nov 16, 2017)	germline	clinical testing	Citation Link,
SCV001924891	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

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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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058963.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

Description

p.Asp315Asp in exon 6 of GLA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.02% (15/90617) of European chromosomes, including 5 hemizygotes, by the Genome Aggregation Databas e (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs151208856).

#	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		5	not provided	5	not provided

From GeneDx, SCV000207804.10

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919434.1

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

Description

Variant summary: The GLA c.945C>T (p.Asp315Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing (1 tool predicts a decreased affinity for a cryptic donor splice site). ESE finder predicts that this variant may affect a binding site for SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19/200260 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000166 (15/90617) with 5 hemizygous occurrences, that exceeds the disease prevalence (1/50000), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, based mainly on the in silico predictions and the observed hemizygous occurrences this variant is classified as likely benign.

#	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 Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001924891.1

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

#	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

Last Updated: Oct 20, 2024

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