5-218357-T-C

Variant summary

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

The NM_004168.4(SDHA):ā€‹c.2T>Cā€‹(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 0.0000084 in 1,309,370 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 (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 35)
Exomes š‘“: 0.0000084 ( 0 hom. )

Consequence

SDHA
NM_004168.4 start_lost

Scores

2
5
9

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.08
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 12 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 339 CDS bases. Genomic position: 225445. Lost 0.170 part of the original CDS.
PP5
Variant 5-218357-T-C is Pathogenic according to our data. Variant chr5-218357-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 412398.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
SDHANM_004168.4 linkc.2T>C p.Met1? start_lost Exon 1 of 15 ENST00000264932.11 NP_004159.2 P31040-1A0A024QZ30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHAENST00000264932.11 linkc.2T>C p.Met1? start_lost Exon 1 of 15 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.2T>C non_coding_transcript_exon_variant Exon 1 of 24 ENSP00000499215.1 A0A494C1T6

Frequencies

GnomAD3 genomes
Cov.:
35
GnomAD3 exomes
AF:
0.00000866
AC:
1
AN:
115518
Hom.:
0
AF XY:
0.0000150
AC XY:
1
AN XY:
66786
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000140
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000840
AC:
11
AN:
1309370
Hom.:
0
Cov.:
31
AF XY:
0.0000108
AC XY:
7
AN XY:
646500
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000161
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000573
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
35

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2
May 04, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the SDHA gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This mutation has been reported in a 23-year-old individual with a GIST and a concurrent renal cell carcinoma and was not detected in 100 population-matched controls (Jiang Q et al. Int J Clin Exp Pathol 2015 Oct;8(10):12188-97). 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. -

May 17, 2023
Breast Care Center, Daerim St. Mary`s Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The SDHA:c.2T>C variant was detected rarely in gnomAD population databases. It is a null variant, resulting in a starting loss located in exon 1, which aligns with a known mechanism of disease. Additionally, it leads to the same amino acid change as a known pathogenic variant. This variant was detected in a 57-year-old Korean woman diagnosed with hormone-positive and invasive ductal breast cancer. She had a family history of first-degree relatives with breast cancer and pancreatic cancer. -

Paragangliomas 5 Pathogenic:2
Apr 24, 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, 10746566, 26722403, 32971818]. -

Jan 16, 2018
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
Dec 02, 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with GIST, paraganglioma and autosomal recessive mitochondrial complex II deficiency (PMID: 10746566, 26722403, 28384794; internal data). ClinVar contains an entry for this variant (Variation ID: 412398). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.0072
T
BayesDel_noAF
Uncertain
0.0
CADD
Benign
21
DANN
Benign
0.62
DEOGEN2
Benign
0.29
T;T;.;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Benign
-0.68
T
PROVEAN
Benign
-0.66
.;N;N;N
REVEL
Uncertain
0.36
Sift
Uncertain
0.0010
.;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
0.063, 0.21
.;B;B;.
Vest4
0.79
MutPred
0.96
Gain of catalytic residue at M1 (P = 0.0054);Gain of catalytic residue at M1 (P = 0.0054);Gain of catalytic residue at M1 (P = 0.0054);Gain of catalytic residue at M1 (P = 0.0054);
MVP
0.75
ClinPred
0.99
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.78

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: rs750380279; hg19: chr5-218472; API