GALT N314D - GET-Evidence

Curation:
Currentness:

GALT N314D

(GALT Asn314Asp)


Short summary

This variant has an allele frequency of ~8% and is ancestral to “Duarte” / “Duarte 2” and “Duarte 1”/“Los Angeles” galactosemia variants. This variant is evolutionarily ancestral, and in vitro studies fail to support an impact of this variant on enzyme activity. Carney et al. instead implicate a 4 base deletion on the 5’ of the GALT gene as being causal and linked to this variant. Galactosemia is typically screened and detected in infants and causes early, severe but nonspecific symptoms (digestive problems, lethargy, failure to thrive).

Variant evidence
Computational 1

This variant is evolutionarily ancestral

Functional 3

Multiple in vitro studies fail to support an impact of N314D on enzyme activity.

See Tyfield L et al. 1999 (10408771), Carney AE et al. 2009 (19224951).

Case/Control 1

High allele frequency (11% in Europeans, ~8% pan-ethnic) contradicts severe pathogenic effect

See Carney AE et al. 2009 (19224951).

Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Low clinical importance, Uncertain benign

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

undefined

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr9:34649442: 7.2% (771/10758) in EVS
  • G @ chr9:34639441: 6.2% (8/128) in GET-Evidence
  • Frequency shown in summary reports: 7.2% (771/10758)

Publications
 

Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ 2nd, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. Review. PubMed PMID: 10408771.

Authors note two different in vitro experiments have failed to show an impact of N314D on GALT activity: “In vitro studies using either the cos [Reichardt
and Woo, 1991] or the yeast expression system [Fridovich-Keil et al., 1995a] have shown that N314D does not impair GALT activity.”

Elsas LJ 2nd, Lai K. The molecular biology of galactosemia. Genet Med. 1998 Nov-Dec;1(1):40-8. Review. PubMed PMID: 11261429.

Classic galactosaemia results from an inability to digest the sugar galactose and convert it to glucose. The mutated N314D allele (also known as the Duarte variant) of the GALT gene is autosomal recessive. It is not a Mendelian inheritance pattern, however. From the abstract: “The Duarte galactosemia variant is caused by N314D. Homozygosity for N314D reduces GALT activity to 50%. When either E203K or a 1721C->T transition (synonymous in L218, “Los Angeles variant”) are present in cis with N314D, GALT activity reverts to normal.”

Carney AE, Sanders RD, Garza KR, McGaha LA, Bean LJ, Coffee BW, Thomas JW, Cutler DJ, Kurtkaya NL, Fridovich-Keil JL. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2009 May 1;18(9):1624-32. Epub 2009 Feb 18. PubMed PMID: 19224951; PubMed Central PMCID: PMC2667289.

 

Genomes
 

 

 

 

 

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom G @ chr9:34649442

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het G @ chr9:34649442

 

 

GS07357 - var-GS07357-1100-36-ASM
het G @ chr9:34639442

 

GS10851 - var-GS10851-1100-36-ASM
het G @ chr9:34639442

 

Other external references
 

    dbSNP
  • rs2070074
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in