Variant 5-218357-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004168.4(SDHA):c.2T>C(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 (★★).

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

SDHA
NM_004168.4 start_lost

Scores

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]

SDHA links:

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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 5-218357-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/exons	MANE	UniProt
SDHA	NM_004168.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/15	ENST00000264932.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHA	ENST00000264932.11 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/15	1	NM_004168.4	P1	P31040-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000866

AC:

AN:

115518

Hom.:

AF XY:

0.0000150

AC XY:

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:

AN:

1309370

Hom.:

Cov.:

AF XY:

0.0000108

AC XY:

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.:

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

Pathogenic, no assertion criteria provided	clinical testing	Breast Care Center, Daerim St. Mary`s Hospital	May 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 04, 2022	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. -

Paragangliomas 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

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; Invitae). 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

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.29

T;T;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Benign

-0.68

MutationTaster

Benign

1.0

D;D;D

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

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.

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