NM_000159.4(GCDH):c.572T>C (p.Met191Thr) AND Glutaric aciduria, type 1

Clinical significance:Pathogenic (Last evaluated: Aug 2, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000179723.12

Allele description [Variation Report for NM_000159.4(GCDH):c.572T>C (p.Met191Thr)]

NM_000159.4(GCDH):c.572T>C (p.Met191Thr)

Gene:
GCDH:glutaryl-CoA dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.13
Genomic location:
Preferred name:
NM_000159.4(GCDH):c.572T>C (p.Met191Thr)
HGVS:
  • NC_000019.10:g.12896058T>C
  • NG_009292.1:g.9899T>C
  • NM_000159.4:c.572T>CMANE SELECT
  • NM_013976.5:c.572T>C
  • NP_000150.1:p.Met191Thr
  • NP_039663.1:p.Met191Thr
  • NC_000019.9:g.13006872T>C
  • NM_000159.2:c.572T>C
  • NM_000159.3:c.572T>C
  • NR_102316.1:n.735T>C
  • NR_102317.1:n.988T>C
  • Q92947:p.Met191Thr
Protein change:
M191T
Links:
UniProtKB: Q92947#VAR_000378; dbSNP: rs149120354
NCBI 1000 Genomes Browser:
rs149120354
Molecular consequence:
  • NM_000159.4:c.572T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_013976.5:c.572T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_102316.1:n.735T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_102317.1:n.988T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Glutaric aciduria, type 1 (GA1)
Synonyms:
GA I; Glutaryl-CoA dehydrogenase deficiency; Glutaric acidemia type I; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009281; MedGen: C0268595; Orphanet: 25; OMIM: 231670

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000631938Invitaecriteria provided, single submitter
Pathogenic
(Aug 2, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000677904Counsylno assertion criteria providedLikely pathogenic
(Mar 13, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000919424Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Apr 16, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001456388Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I.

Schwartz M, Christensen E, Superti-Furga A, Brandt NJ.

Hum Genet. 1998 Apr;102(4):452-8.

PubMed [citation]
PMID:
9600243

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000631938.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces methionine with threonine at codon 191 of the GCDH protein (p.Met191Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs149120354, ExAC 0.02%). This variant has been reported as homozygous and in combination with another GCDH variant in individuals affected with glutaric aciduria type I (PMID: 9600243, 21031586, 28411331). ClinVar contains an entry for this variant (Variation ID: 198396). This variant has been observed in two individuals with GCDH enzymatic activity <0.5% of wild-type, findings that are highly specific for glutaric aciduria type I (PMID: 9600243). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000677904.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919424.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: GCDH c.572T>C (p.Met191Thr) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase central domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 277158 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1, allowing no conclusion about variant significance. The c.572T>C has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001456388.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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