Table 10. [Notable GCDH Pathogenic Variants]. - GeneReviews®

Reference Sequence	Variant Class	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_000159.3	Variants w/GPC ¹	c.91+5G>T		Low-excreter & founder variant in Ojibway-Cree First Nations Canadians [Greenberg et al 1995, Greenberg et al 2002]
NM_000159.3 NP_000150.1	c.680G>C	p.Arg227Pro	Low-excreter; 85%-10% residual activity [Christensen et al 2004]
c.1198G>A	p.Val400Met	Low-excreter; 8%-10% residual activity [Christensen et al 1997] A common variant among low excreters in Spain [Busquets et al 2000a]
c.1213A>G	p.Met405Val	Low-excreter [Schillaci et al 2016] A common variant among low-excreter African Americans [Schillaci et al 2016]
Additional founder & common variants	c.541G>C	p.Glu181Gln	Common variant in Iran & Turkey [Baradaran et al 2014]
c.877G>A	p.Ala293Thr	Founder variant in South African Xhosa population; prevalence: ~1:5,184 [van der Watt et al 2010]
c.1093G>A	p.Glu365Lys	Founder variant in Irish Traveler communities in the Republic of Ireland [Naughten et al 2004]
c.1204C>T	p.Arg402Trp	Most common pan ethnic pathogenic variant [Schwartz et al 1998, Busquets et al 2000b, Gupta et al 2015, Tp et al 2017]
c.1240G>A	p.Glu414Lys	Founder variant in Lumbee Native Americans of North Carolina [Basinger et al 2006]
c.1262C>T	p.Ala421Val	Founder variant in Pennsylvania Amish: carrier frequency may be as high as 1 in 10 in some Pennsylvania Amish communities [Morton et al 1991]
Possible dominant- negative variant	c.553_570del18	p.Gly185_Ser190del	Heterozygosity results in GCDH enzyme activity significantly < 50%; a dominant-negative effect has been suggested but no clinical phenotype was present [Bross et al 2012].

Reference
Sequence

Variant
Class

DNA Nucleotide
Change

Predicted Protein
Change

Comment [Reference]

NM_000159.3

Variants
w/GPC ¹

c.91+5G>T

Low-excreter & founder variant in Ojibway-Cree First Nations Canadians [Greenberg et al 1995, Greenberg et al 2002]

NM_000159.3
NP_000150.1

c.680G>C

p.Arg227Pro

Low-excreter; 85%-10% residual activity [Christensen et al 2004]

c.1198G>A

p.Val400Met

Low-excreter; 8%-10% residual activity [Christensen et al 1997]
A common variant among low excreters in Spain [Busquets et al 2000a]

c.1213A>G

p.Met405Val

Low-excreter [Schillaci et al 2016]
A common variant among low-excreter African Americans [Schillaci et al 2016]

Additional
founder &
common
variants

c.541G>C

p.Glu181Gln

Common variant in Iran & Turkey [Baradaran et al 2014]

c.877G>A

p.Ala293Thr

Founder variant in South African Xhosa population; prevalence: ~1:5,184 [van der Watt et al 2010]

c.1093G>A

p.Glu365Lys

Founder variant in Irish Traveler communities in the Republic of Ireland [Naughten et al 2004]

c.1204C>T

p.Arg402Trp

Most common pan ethnic pathogenic variant [Schwartz et al 1998, Busquets et al 2000b, Gupta et al 2015, Tp et al 2017]

c.1240G>A

p.Glu414Lys

Founder variant in Lumbee Native Americans of North Carolina [Basinger et al 2006]

c.1262C>T

p.Ala421Val

Founder variant in Pennsylvania Amish: carrier frequency may be as high as 1 in 10 in some Pennsylvania Amish communities [Morton et al 1991]

Possible
dominant-
negative
variant

c.553_570del18

p.Gly185_Ser190del

Heterozygosity results in GCDH enzyme activity significantly < 50%; a dominant-negative effect has been suggested but no clinical phenotype was present [Bross et al 2012].

From: Glutaric Acidemia Type 1

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