chr5-218356-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_004168.4(SDHA):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

SDHA
NM_004168.4 initiator_codon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.636

Variant links:

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 links:

ENSG00000286001 (HGNC:):

ENSG00000286001 links:

CCDC127 (HGNC:30520): (coiled-coil domain containing 127) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CCDC127 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 114 codons. Genomic position: 225446. Lost 0.170 part of the original CDS.

PP5

Variant 5-218356-A-T is Pathogenic according to our data. Variant chr5-218356-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 15	ENST00000264932.11	NP_004159.2	P31040-1A0A024QZ30
CCDC127	NM_145265.3 link	c.-274T>A		upstream_gene_variant		ENST00000296824.4	NP_660308.1	Q96BQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDHA	ENST00000264932.11 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6	P31040-1
ENSG00000286001	ENST00000651543.1 link	n.1A>T		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1	A0A494C1T6
CCDC127	ENST00000296824.4 link	c.-274T>A		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2	Q96BQ5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000306

AC:

AN:

1308140

Hom.:

Cov.:

AF XY:

0.00000619

AC XY:

AN XY:

645810

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000151

Gnomad4 FIN exome

AF:

0.0000294

Gnomad4 NFE exome

AF:

0.00000191

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paragangliomas 5

Pathogenic:2

Mar 31, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28384794, 35014173, 10746566, 32971818]. -

Nov 25, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Nov 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with SDHA-related conditions (PMID: 10746566, 26722403, 28384794). ClinVar contains an entry for this variant (Variation ID: 371794). This variant disrupts the N-terminal part of the SDHA protein, which is important for FAD binding (PMID: 25488574, 15989954, 21858060). While functional studies have not been performed to directly test the effect of this variant on SDHA protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Oct 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the SDHA gene and results from a A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This alteration was reported in a 30 year old with an adrenal paraganglioma. In addition, two different alterations that also affect the initiation codon, c.1A>G and c.1A>C (p.M1?) have been reported in individuals with paraganglioma (Snezhkina AV et al. Int J Mol Sci 2020 Sep;21(18); Bausch B. et al. JAMA Oncol 2017 Sep;3(9):1204-1212). The c.1A>C alteration has also been reported in an individual with Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Neurodegeneration with ataxia and late-onset optic atrophy

Pathogenic:1

Jan 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHA c.1A>T (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame Methionine is located at codon 114 in exon 4 of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 114846 control chromosomes. c.1A>T has been reported in the literature in at-least one individual affected with Pheochromocytoma/paraganglioma (example: Bausch_2017). A different variant affecting this codon c.1A>C has been classified Pathogenic by our lab. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28384794). ClinVar contains an entry for this variant (Variation ID: 371794). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.26

T;T;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.92

PROVEAN

Benign

-0.26

.;N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.093

.;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.83

MutPred

0.99

Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);

MVP

0.69

ClinPred

0.74

GERP RS

2.5

Varity_R

0.32

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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