NM_004168.4:c.667delG

Variant names:

• chr5-228228-TG-T
• rs587782077
• NM_004168.4:c.667delG

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_004168.4(SDHA):c.667delG (p.Asp223IlefsTer3) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000131 (AC=2) in the gnomAD database across 152,152 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000226. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.42
• Publications: 4 publications found

Genes affected

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• mitochondrial disease

  Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286001 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 6 of 15) at amino acid 223 of 664, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~224 amino acids (440 amino acids lost).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000226 — very rare for AD+AR gene (base 0.0001, raised to 0.000403 by highest known P/LP ClinVar AF 0.000403) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (12/12 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004168.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SDHA NM_004168.4	MANE Select	c.667delG p.Asp223IlefsTer3	frameshift	Exon 6 of 15	Prot: NP_004159.2 UniProt:
	SDHA NM_001294332.2		c.523delG p.Asp175IlefsTer3	frameshift	Exon 5 of 14	Prot: NP_001281261.1 UniProt:
	SDHA NM_001330758.2		c.667delG p.Asp223IlefsTer3	frameshift	Exon 6 of 13	Prot: NP_001317687.1 UniProt:

SDHA NM_004168.4

MANE Select

HGVSc / HGVSpc.667delGp.Asp223IlefsTer3

Exon rankExon 6 of 15

frameshift

Prot: NP_004159.2UniProt: P31040-1

SDHA NM_001294332.2

HGVSc / HGVSpc.523delGp.Asp175IlefsTer3

Exon rankExon 5 of 14

frameshift

Prot: NP_001281261.1UniProt: P31040-2

SDHA NM_001330758.2

HGVSc / HGVSpc.667delGp.Asp223IlefsTer3

Exon rankExon 6 of 13

frameshift

Prot: NP_001317687.1UniProt: D6RFM5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SDHA ENST00000264932.11	TSL:1MANE Select	c.667delG p.Asp223IlefsTer3	frameshift	Exon 6 of 15	Prot: ENSP00000264932.6 UniProt:
	ENSG00000286001 ENST00000651543.1		n.667delG	non_coding_transcript_exon	Exon 6 of 24	Prot: ENSP00000499215.1 UniProt:
	SDHA ENST00000874235.1		c.667delG p.Asp223IlefsTer3	frameshift	Exon 6 of 16	Prot: ENSP00000544294.1 UniProt:

SDHA ENST00000264932.11

TSL:1MANE Select

HGVSc / HGVSpc.667delGp.Asp223IlefsTer3

Exon rankExon 6 of 15

frameshift

Prot: ENSP00000264932.6UniProt: P31040-1

ENSG00000286001 ENST00000651543.1

HGVSc / HGVSpn.667delG

Exon rankExon 6 of 24

non_coding_transcript_exon

Prot: ENSP00000499215.1UniProt: A0A494C1T6

SDHA ENST00000874235.1

HGVSc / HGVSpc.667delGp.Asp223IlefsTer3

Exon rankExon 6 of 16

frameshift

Prot: ENSP00000544294.1UniProt: A0ACI8PTE4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152152	Cov:33
GnomAD2 exomes	AF: 0.0000239	AC:6	Hom:	AN:251164	Cov:
GnomAD4 exome Warning	AF: 0.00000753	AC:11	Hom:0	AN:1461560	Cov:32
GnomAD4 genome Warning	AF: 0.0000131	AC:2	Hom:0	AN:152152	Cov:33
TOPMed (Bravo)	AF: 0.0000151	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000674	AC:1	Hom:0	AN:14846	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.000132	3	22746	0.000103	3	29212

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Dilated cardiomyopathy 1GG (1)
1	-	-	Dilated cardiomyopathy 1GG;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
1	-	-	Neurodegeneration with ataxia and late-onset optic atrophy (1)
1	-	-	Pheochromocytoma/paraganglioma syndrome 5 (1)
1	-	-	Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 (1)
1	-	-	SDHA-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	5.4

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs587782077;

hg19: chr5-228343;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar