rs137852860

chr7-40459197-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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:5 B:1 O:1
• Conservation: PhyloP100: 0.756

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057564437).
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUGCT	ENST00000335693.9	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/14	1	NM_001193313.2	P1
SUGCT	ENST00000628514.3	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/15	1
SUGCT	ENST00000416370.2	c.985C>T	p.Arg329Trp	missense_variant, splice_region_variant	11/13	1
SUGCT	ENST00000401647.7	c.841C>T	p.Arg281Trp	missense_variant, splice_region_variant	10/13	1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152036 Hom.: 4 Cov.: 32

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.: 10 AF XY: 0.00452 AC XY: 603 AN XY: 133384

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.: 28 Cov.: 24 AF XY: 0.00563 AC XY: 4001 AN XY: 711094

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.: 4 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74384

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.: 8

Bravo AF: 0.00421

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00167 AC: 6

ESP6500EA AF: 0.00715 AC: 58

ExAC AF: 0.00536 AC: 647

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glutaryl-CoA oxidase deficiency Pathogenic:3 Other: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	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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	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) -

SUGCT-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

The SUGCT c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Trp. This gene is also known as C7orf10. 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). 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	T
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.0068
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	0.15	A;A;A
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	T
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

Other links and lift over

dbSNP: rs137852860; hg19: chr7-40498796;