PhenoModifier-Variant Detail

Variant "GBA:c.680A>G(p.Asn227Ser)"

Search result: 1 record

Variant information

Gene:

GBA

Variant:

GBA:c.680A>G(p.Asn227Ser)

Genomic location:

chr1:155208006(hg19)

HGVS:

SO Term	RefSeq
protein_coding	NM_000157.3:c.680A>G(p.Asn227Ser)
protein_coding	NM_001005741.2:c.680A>G(p.Asn227Ser)
protein_coding	NM_001005742.2:c.680A>G(p.Asn227Ser)
protein_coding	NM_001171812.1:c.533A>G(p.Asn178Ser)
protein_coding	NM_001171811.1:c.419A>G(p.Asn140Ser)

dbSNP ID:

rs364897

GWAS trait:

no data

Modifier statisitcs

Record:

1

Disorder:

1

Reference:

1

Effect type:

Expressivity(1)

Modifier effect:

Altered gene activity(1)

Detail：

Target disease:

Gaucher's Disease (DOID_1926)

Effect type:

Expressivity

Modifier effect:

Altered gene activity

Evidence:

Gene expression studies

Effect:

c.680A>G (p.N188S) is a very mild mutation or another modifier variant.

Reference:

PMID15146461

Title:

Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and modifier polymorphisms.

Species studied:

Human

Abstract:

Gaucher disease, the most prevalent sphingolipidosis, is caused by the deficient activity of acid beta-glucosidase, mainly due to mutations in the GBA gene. Over 200 mutations have been identified worldwide, more than 25 of which were in Spanish patients. In order to demonstrate causality for Gaucher disease, some of them: c.662C>T (p.P182L), c.680A>G (p.N188S), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1093G>A (p.E326K), c.1289C>T (p.P391L), c.1292A>T (p.N392I), c.1322T>C (p.I402T), and the double mutants [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), were expressed in Sf9 cells using a baculovirus expression system. Other well-established Gaucher disease mutations, namely c.1226A>G (p.N370S), c.1342G>C (p.D409H), and c.1448T>C (p.L444P), were also expressed for comparison. The levels of residual acid beta-glucosidase activity of the mutant enzymes produced by the cDNAs carrying alleles c.662C>T (p.P182L), c.886C>T (p.R257X), c.1054T>C (p.Y313H), c.1289C>T (p.P391L), and c.1292A>T (p.N392I) were negligible. The c.1226A>G (p.N370S), c.1322T>C (p.I402T), c.1342G>C (p.D409H), c.1448T>C (p.L444P), and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]) alleles produced enzymes with levels ranging from 6 to 14% of the wild-type. The three remaining alleles, c.680A>G (p.N188S), c.1093G>A (p.E326K), and [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]), showed higher activity (66.6, 42.7, and 23.2%, respectively). Expression studies revealed that the c.1093G>A (p.E326K) change, which was never found alone in a Gaucher disease-causing allele, when found in a double mutant such as [c.680A>G; c.1093G>A] ([p.N188S; p.E326K]) and [c.1448T>C; c.1093G>A] ([p.L444P; p.E326K]), decreases activity compared to the activity found for the other mutation alone. These results suggest that c.1093G>A (p.E326K) should be considered a modifier variant rather than a neutral polymorphism, as previously considered. Mutation c.680A>G (p.N188S), which produces a mutant enzyme with the highest level of activity, is probably a very mild mutation or another modifier variant.