5-236472-G-T

Variant names:

• chr5-236472-G-T
• rs35964044
• NM_004168.4:c.1305G>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004168.4(SDHA):​c.1305G>T​(p.Leu435Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,896 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 33)
  • Exomes 𝑓: 0.016 (265 hom.)
• Consequence: SDHA NM_004168.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 0.0500

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:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-236472-G-T is Benign according to our data. Variant chr5-236472-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224954.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, Uncertain_significance=1}. Variant chr5-236472-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2350/152354) while in subpopulation SAS AF= 0.0251 (121/4830). AF 95% confidence interval is 0.0214. There are 27 homozygotes in gnomad4. There are 1241 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1305G>T	p.Leu435Leu	synonymous_variant	Exon 10 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHA	ENST00000264932.11	c.1305G>T	p.Leu435Leu	synonymous_variant	Exon 10 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*38G>T		non_coding_transcript_exon_variant	Exon 9 of 24			ENSP00000499215.1
ENSG00000286001	ENST00000651543.1	n.*38G>T		3_prime_UTR_variant	Exon 9 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2355 AN: 152236 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0188 AC: 4729 AN: 251098 Hom.: 79 AF XY: 0.0203 AC XY: 2751 AN XY: 135722

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.0463

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0163 AC: 23876 AN: 1461542 Hom.: 265 Cov.: 31 AF XY: 0.0169 AC XY: 12309 AN XY: 727092

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0466

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0253

Gnomad4 FIN exome AF: 0.0369

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0154 AC: 2350 AN: 152354 Hom.: 27 Cov.: 33 AF XY: 0.0167 AC XY: 1241 AN XY: 74500

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0369

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0170 Hom.: 14

Bravo AF: 0.0133

EpiCase AF: 0.0197

EpiControl AF: 0.0206

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Nov 13, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Sep 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 25, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 08, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, BS2_Supporting, BP4, BP7 c.1305G>T, located in exon 10 of the SDHA gene, is predicted to result in no amino acid change, p.(Leu435=)(BP7). The variant allele was found in 5005/267970 alleles, with a filtering allele frequency of 1,9% at 99% confidence, within the non-Finland European population in the gnomAD v2.1.1 database (non-cancer data set) (BA1) and has been observed in the homozygous state in 79 individuals (BS2_Supporting) The SpliceAI algorithm predicts no significant impact on splicing (BP4). Based on currently available information, the variant c.1305G>T should be considered a benign variant according to ACMG/AMP classification guidelines. -

Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Leigh syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dilated cardiomyopathy 1GG;C3279992:Paragangliomas 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1

Dec 01, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paragangliomas 5 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pheochromocytoma-paraganglioma Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.6
DANN	Benign	0.46

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: rs35964044; hg19: chr5-236587; COSMIC: COSV53772863; COSMIC: COSV53772863;