5-218356-A-T

Position:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The NM_004168.4(SDHA):​c.1A>T​(p.Met1?) variant causes a start lost 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 start_lost

Scores

3
3
10

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_004168.4 (SDHA) was described as [Pathogenic] in ClinVar as 1408872
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/exons MANE UniProt
SDHANM_004168.4 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/15 ENST00000264932.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SDHAENST00000264932.11 linkuse as main transcriptc.1A>T p.Met1? start_lost 1/151 NM_004168.4 P1P31040-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152158
Hom.:
0
Cov.:
34
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:
4
AN:
1308140
Hom.:
0
Cov.:
31
AF XY:
0.00000619
AC XY:
4
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:
2
AN:
152158
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
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:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Paragangliomas 5 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 31, 2023This 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]. -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylNov 25, 2015- -
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2023This 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
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 24, 2021The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Benign
14
DANN
Benign
0.65
DEOGEN2
Benign
0.26
T;T;.;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.56
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
1.0
D;D;D
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
D
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.

Other links and lift over

dbSNP: rs1061517; hg19: chr5-218471; API