5-218356-A-C

Variant names:

• chr5-218356-A-C
• rs1061517
• NM_004168.4:c.1A>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.1A>C​(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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: SDHA NM_004168.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.636

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 5-218356-A-C is Pathogenic according to our data. Variant chr5-218356-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 8744.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.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 15	ENST00000264932.11	NP_004159.2
CCDC127	NM_145265.3	c.-274T>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.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.1A>C		non_coding_transcript_exon_variant	Exon 1 of 24			ENSP00000499215.1
CCDC127	ENST00000296824.4	c.-274T>G		upstream_gene_variant		1	NM_145265.3	ENSP00000296824.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000382 AC: 5 AN: 1308140 Hom.: 0 Cov.: 31 AF XY: 0.00000310 AC XY: 2 AN XY: 645810

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000477

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Dec 10, 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 pheochromocytoma, gastrointestinal stromal tumor, and clinical features of complex II deficiency (PMID: 10746566, 28384794, 31413764). ClinVar contains an entry for this variant (Variation ID: 8744). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SDHA function (PMID: 10746566). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 14, 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>C) is located in coding exon 1 of the SDHA gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. There is an in-frame methionine 114 amino acids downstream from this initiation site which may result in an N-terminal truncation; however, direct evidence is unavailable. This alteration has 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). This alteration has also been observed individuals with paraganglioma and gastrointestinal stromal tumor (GIST) (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). 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 variant is interpreted as a disease-causing mutation. -

Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1

May 03, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHA c.1A>C (p.Met1?) 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. The variant was absent in 114846 control chromosomes. c.1A>C has been reported in the literature as a compound heterozygous genotype in an individual affected with features of Leigh Syndrome with Succinate dehydrogenase deficiency (example, Parfait_2000) and as a heterozygous genotype in individuals affected with features of extra-adrenal thoracid paraganglioma and/or Gastrointestinal stromal tumors (GISTs) (example, Bausch_2017, Carrera_2019). At least one publication reports experimental evidence evaluating an impact on transcript levels (Parfait_2000). The most pronounced variant effect results in mutant transcript representing only 10% of total Flavoprotein (Fp) transcripts, suggesting a high instability of this transcript. The following publications have been ascertained in the context of this evaluation (PMID: 28384794, 31413764, 10746566). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Paragangliomas 5 Pathogenic:1

Aug 10, 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]. -

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	0.48
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.61	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
PROVEAN	Benign	-0.26	.;N;N;N
REVEL	Uncertain	0.36
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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

Other links and lift over

dbSNP: rs1061517; hg19: chr5-218471;