Reported as a variant possibly associated with an increased risk to develop autism spectrum disorder (Matsunami et al., 2014); Published functional studies demonstrate that the variant leads to the production of an insoluble and inactive protein (Marlaire et al., 2014); This variant is associated with the following publications: (PMID: 20818383, 23893049, 18926513, 31980526, 34426522, 24467814, 31028937, 28766179)
ClinVar Genomic variation as it relates to human health
NM_001193313.2(SUGCT):c.985C>T (p.Arg329Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(4); Benign(1)
Pathogenic(4); Benign(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001193313.2(SUGCT):c.985C>T (p.Arg329Trp)
Variation ID: 1849 Accession: VCV000001849.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p14.1 7: 40459197 (GRCh38) [ NCBI UCSC ] 7: 40498796 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 9, 2017 Nov 24, 2024 Dec 8, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001193313.2:c.985C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001180242.2:p.Arg329Trp missense NM_001193311.1:c.1006C>T NM_001193311.2:c.985C>T NP_001180240.2:p.Arg329Trp missense NM_001193312.2:c.841C>T NP_001180241.2:p.Arg281Trp missense NM_024728.3:c.874C>T NP_079004.2:p.Arg292Trp missense NC_000007.14:g.40459197C>T NC_000007.13:g.40498796C>T NG_023422.2:g.329222C>T Q9HAC7:p.Arg336Trp - Protein change
- R299W, R281W, R292W, R329W
- Other names
-
p.Arg299Trp
- Canonical SPDI
- NC_000007.14:40459196:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00060 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00421
The Genome Aggregation Database (gnomAD), exomes 0.00463
The Genome Aggregation Database (gnomAD) 0.00490
Exome Aggregation Consortium (ExAC) 0.00564
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SUGCT | - | - |
GRCh38 GRCh37 |
154 | 199 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2023 | RCV000001923.9 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 8, 2023 | RCV000413225.13 | |
|
SUGCT-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 29, 2024 | RCV003421894.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaryl-CoA oxidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893764.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Benign
(Nov 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001037326.3
First in ClinVar: Dec 17, 2019 Last updated: May 16, 2022 |
|
|
|
Pathogenic
(May 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490447.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported as a variant possibly associated with an increased risk to develop autism spectrum disorder (Matsunami et al., 2014); Published functional studies demonstrate that the … (more)
Reported as a variant possibly associated with an increased risk to develop autism spectrum disorder (Matsunami et al., 2014); Published functional studies demonstrate that the variant leads to the production of an insoluble and inactive protein (Marlaire et al., 2014); This variant is associated with the following publications: (PMID: 20818383, 23893049, 18926513, 31980526, 34426522, 24467814, 31028937, 28766179) (less)
|
|
|
Pathogenic
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glutaryl-CoA oxidase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003928585.2
First in ClinVar: Jun 03, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: C7orf10 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. Four of five … (more)
Variant summary: C7orf10 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 276776 control chromosomes in the gnomAD database, including 10 homozygotes. c.895C>T has been reported in the literature in multiple individuals affected with Glutaryl-CoA Oxidase Deficiency and mitochondrial complex I disorder (Sherman_2008, Calvo_2010, Hou_2020), and some were reported as compound heterozygous with truncating variants. 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, finding that the variant prevents the synthesis of soluble C7orf10 protein (Marlaire_2014). The following publications have been ascertained in the context of this evaluation (PMID: 18926513, 20818383, 23893049, 31980526). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=1) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413780.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP4, PM2_moderate, PS3, PS4_moderate
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Aug 29, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SUGCT-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117197.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The SUGCT c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Trp. This variant has been reported in the compound heterozygous or homozygous … (more)
The SUGCT c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Trp. This variant has been reported in the compound heterozygous or homozygous state in several individuals with glutaric aciduria type III (Sherman et al. 2008. PubMed ID: 18926513, described as c.895C>T based on transcript NM_024728). An in vitro study suggested that the p.Arg336Trp substitution impairs protein folding (Marlaire et al. 2014. PubMed ID: 23893049). It is currently thought that glutaric aciduria type III is potentially a benign biochemical phenomenon: pathogenic variants are reported in both healthy individuals and affected patients who present with inconsistent symptoms (Sherman et al. 2008. PubMed ID: 18926513; Marlaire et al. 2014. PubMed ID: 23893049). This variant is reported in 0.81% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including several homozygous individuals. Although we classify the c.1006C>T variant as pathogenic based on its effect on the SUGCT protein, the contribution of this variant to clinical disease is uncertain. (less)
|
|
|
Pathogenic
(Nov 01, 2008)
|
no assertion criteria provided
Method: literature only
|
GLUTARIC ACIDURIA III
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022081.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2017 |
Comment on evidence:
Sherman et al. (2008) identified 3 distantly related Amish individuals with glutaric aciduria III (GA3; 231690) who were homozygous for a C-to-T transversion at nucleotide … (more)
Sherman et al. (2008) identified 3 distantly related Amish individuals with glutaric aciduria III (GA3; 231690) who were homozygous for a C-to-T transversion at nucleotide 895 in exon 11 of the C7ORF10 gene, resulting in an arginine-to-tryptophan substitution at codon 299 (R299W). This mutation was found in homozygosity in another patient of German ancestry originally described by Knerr et al. (2002), but resided on a different haplotype. This mutation was also found in compound heterozygosity in a patient of mixed European ancestry (see 609187.0002). The mutation is not a known polymorphism and occurs at a residue highly conserved in all species tested. Among 150 Amish control individuals, Sherman et al. (2008) identified 26 who were heterozygous and 1 who was homozygous for the R299W mutation. This individual was 35 years of age, healthy, and had a high glutaric acid excretion. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Glutaryl-CoA oxidase deficiency
Affected status: yes
Allele origin:
germline
|
GenomeConnect, ClinGen
Accession: SCV002074861.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Failure to thrive (present) , Abnormal optic nerve morphology (present) , Sensorineural hearing loss disorder (present) , Abnormality of the nervous system (present) , Generalized … (more)
Failure to thrive (present) , Abnormal optic nerve morphology (present) , Sensorineural hearing loss disorder (present) , Abnormality of the nervous system (present) , Generalized hypotonia (present) , Movement disorder (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2020-05-06
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
Variant summary: C7orf10 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 276776 control chromosomes in the gnomAD database, including 10 homozygotes. c.895C>T has been reported in the literature in multiple individuals affected with Glutaryl-CoA Oxidase Deficiency and mitochondrial complex I disorder (Sherman_2008, Calvo_2010, Hou_2020), and some were reported as compound heterozygous with truncating variants. 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, finding that the variant prevents the synthesis of soluble C7orf10 protein (Marlaire_2014). The following publications have been ascertained in the context of this evaluation (PMID: 18926513, 20818383, 23893049, 31980526). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=1) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP4, PM2_moderate, PS3, PS4_moderate
Comment:
The SUGCT c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Trp. This variant has been reported in the compound heterozygous or homozygous state in several individuals with glutaric aciduria type III (Sherman et al. 2008. PubMed ID: 18926513, described as c.895C>T based on transcript NM_024728). An in vitro study suggested that the p.Arg336Trp substitution impairs protein folding (Marlaire et al. 2014. PubMed ID: 23893049). It is currently thought that glutaric aciduria type III is potentially a benign biochemical phenomenon: pathogenic variants are reported in both healthy individuals and affected patients who present with inconsistent symptoms (Sherman et al. 2008. PubMed ID: 18926513; Marlaire et al. 2014. PubMed ID: 23893049). This variant is reported in 0.81% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including several homozygous individuals. Although we classify the c.1006C>T variant as pathogenic based on its effect on the SUGCT protein, the contribution of this variant to clinical disease is uncertain.
Comment:
Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Reported as a variant possibly associated with an increased risk to develop autism spectrum disorder (Matsunami et al., 2014); Published functional studies demonstrate that the variant leads to the production of an insoluble and inactive protein (Marlaire et al., 2014); This variant is associated with the following publications: (PMID: 20818383, 23893049, 18926513, 31980526, 34426522, 24467814, 31028937, 28766179)
Comment:
Variant summary: C7orf10 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change to a highly conserved residue in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 276776 control chromosomes in the gnomAD database, including 10 homozygotes. c.895C>T has been reported in the literature in multiple individuals affected with Glutaryl-CoA Oxidase Deficiency and mitochondrial complex I disorder (Sherman_2008, Calvo_2010, Hou_2020), and some were reported as compound heterozygous with truncating variants. 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, finding that the variant prevents the synthesis of soluble C7orf10 protein (Marlaire_2014). The following publications have been ascertained in the context of this evaluation (PMID: 18926513, 20818383, 23893049, 31980526). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as benign (n=1) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP4, PM2_moderate, PS3, PS4_moderate
Comment:
The SUGCT c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Trp. This variant has been reported in the compound heterozygous or homozygous state in several individuals with glutaric aciduria type III (Sherman et al. 2008. PubMed ID: 18926513, described as c.895C>T based on transcript NM_024728). An in vitro study suggested that the p.Arg336Trp substitution impairs protein folding (Marlaire et al. 2014. PubMed ID: 23893049). It is currently thought that glutaric aciduria type III is potentially a benign biochemical phenomenon: pathogenic variants are reported in both healthy individuals and affected patients who present with inconsistent symptoms (Sherman et al. 2008. PubMed ID: 18926513; Marlaire et al. 2014. PubMed ID: 23893049). This variant is reported in 0.81% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including several homozygous individuals. Although we classify the c.1006C>T variant as pathogenic based on its effect on the SUGCT protein, the contribution of this variant to clinical disease is uncertain.
Comment:
Variant interpreted as Pathogenic and reported on 05-06-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mendelian disease research in the Plain populations of Lancaster County, Pennsylvania. | Puffenberger EG | American journal of medical genetics. Part A | 2021 | PMID: 34532947 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype. | Niska-Blakie J | Cellular and molecular life sciences : CMLS | 2020 | PMID: 31722069 |
| Development of a Novel Next-Generation Sequencing Assay for Carrier Screening in Old Order Amish and Mennonite Populations of Pennsylvania. | Crowgey EL | The Journal of molecular diagnostics : JMD | 2019 | PMID: 31028937 |
| Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment. | Waters PJ | JIMD reports | 2018 | PMID: 28766179 |
| Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population. | Matsunami N | Molecular autism | 2014 | PMID: 24467814 |
| C7orf10 encodes succinate-hydroxymethylglutarate CoA-transferase, the enzyme that converts glutarate to glutaryl-CoA. | Marlaire S | Journal of inherited metabolic disease | 2014 | PMID: 23893049 |
| High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
| Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in c7orf10. | Sherman EA | American journal of human genetics | 2008 | PMID: 18926513 |
| Quantification of heterocyclic amines from thermally processed meats selected from a small-scale population-based study. | Busquets R | Molecular nutrition & food research | 2008 | PMID: 18925613 |
| Glutaric aciduria type III: a distinctive non-disease? | Knerr I | Journal of inherited metabolic disease | 2002 | PMID: 12555941 |
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Text-mined citations for rs137852860 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.