5-218357-T-C

Variant names:

• chr5-218357-T-C
• rs750380279
• NM_004168.4:c.2T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.08

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]

ENSG00000286001 (HGNC:):

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

ACMG classification

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 5-218357-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
SDHA	NM_004168.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	ENST00000264932.11	NP_004159.2
CCDC127	NM_145265.3	c.-275A>G		upstream_gene_variant		ENST00000296824.4	NP_660308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.2T>C		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1
CCDC127	ENST00000296824.4	c.-275A>G		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2

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

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

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

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. -

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. -

Paragangliomas 5 Pathogenic:2

Jan 16, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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]. -

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

Other links and lift over

dbSNP: rs750380279; hg19: chr5-218472;