rs137852860

Positions:

chr7-40459197-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001193313.2(SUGCT):c.985C>T(p.Arg329Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,578,104 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 28 hom. )

Consequence

SUGCT
NM_001193313.2 missense, splice_region

Scores

Splicing: ADA: 0.0003452

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1B:1O:1

Conservation

PhyloP100: 0.756

Variant links:

Genes affected

SUGCT (HGNC:16001): (succinyl-CoA:glutarate-CoA transferase) This gene encodes a protein that is similar to members of the CaiB/baiF CoA-transferase protein family. Mutations in this gene are associated with glutaric aciduria type III. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

SUGCT links:

SUGCT (HGNC:):

SUGCT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057564437).

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUGCT	NM_001193313.2 linkuse as main transcript	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/14	ENST00000335693.9	NP_001180242.2	Q9HAC7B4DJF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SUGCT	ENST00000335693.9 linkuse as main transcript	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/14	1	NM_001193313.2	ENSP00000338475.5	Q9HAC7
SUGCT	ENST00000628514.3 linkuse as main transcript	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/15	1		ENSP00000486291.2	Q9HAC7
SUGCT	ENST00000416370.2 linkuse as main transcript	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/13	1		ENSP00000393032.2	H0Y4N1
SUGCT	ENST00000401647.7 linkuse as main transcript	c.841C>T	p.Arg281Trp	missense_variant, splice_region_variant	10/13	1		ENSP00000385222.3	Q9HAC7

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00605

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00750

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00463

AC:

1135

AN:

245402

Hom.:

AF XY:

0.00452

AC XY:

603

AN XY:

133384

show subpopulations

Gnomad AFR exome

AF:

0.000913

Gnomad AMR exome

AF:

0.000383

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.000398

Gnomad FIN exome

AF:

0.00632

Gnomad NFE exome

AF:

0.00828

Gnomad OTH exome

AF:

0.00403

GnomAD4 exome

AF:

0.00571

AC:

8142

AN:

1425950

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

4001

AN XY:

711094

show subpopulations

Gnomad4 AFR exome

AF:

0.00110

Gnomad4 AMR exome

AF:

0.000405

Gnomad4 ASJ exome

AF:

0.00132

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.000472

Gnomad4 FIN exome

AF:

0.00597

Gnomad4 NFE exome

AF:

0.00684

Gnomad4 OTH exome

AF:

0.00488

GnomAD4 genome

AF:

0.00461

AC:

702

AN:

152154

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

329

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00605

Gnomad4 NFE

AF:

0.00750

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00674

Hom.:

Bravo

AF:

0.00421

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00167

AC:

ESP6500EA

AF:

0.00715

AC:

ExAC

AF:

0.00536

AC:

647

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutaryl-CoA oxidase deficiency

Pathogenic:3Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -

not provided

Pathogenic:1Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 08, 2023	PP4, PM2_moderate, PS3, PS4_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R329W); This variant is associated with the following publications: (PMID: 31980526, 34426522, 31028937, 24467814, 28766179, 23893049, 38370847, 18926513, 20818383, 34269512, 39101156) -

SUGCT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;.;T

Eigen

Benign

0.0068

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.058

T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.3

.;M;M

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.013

D;.;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.68

MVP

0.64

ClinPred

0.031

GERP RS

2.5

Varity_R

0.73

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00035

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over