5-224432-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004168.4(SDHA):​c.223C>T​(p.Arg75*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,508 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

SDHA
NM_004168.4 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 2.13

Publications

13 publications found
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 Gene-Disease associations (from GenCC):
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • pheochromocytoma/paraganglioma syndrome 5
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • mitochondrial complex II deficiency, nuclear type 1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • neurodegeneration with ataxia and late-onset optic atrophy
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Leigh syndrome
    Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • gastrointestinal stromal tumor
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Leigh syndrome with leukodystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • mitochondrial complex II deficiency
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • dilated cardiomyopathy 1GG
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 5-224432-C-T is Pathogenic according to our data. Variant chr5-224432-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209127.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.223C>T p.Arg75* stop_gained Exon 3 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.223C>T p.Arg75* stop_gained Exon 3 of 15 1 NM_004168.4 ENSP00000264932.6 P31040-1
ENSG00000286001ENST00000651543.1 linkn.223C>T non_coding_transcript_exon_variant Exon 3 of 24 ENSP00000499215.1 A0A494C1T6

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.0000916
AC:
23
AN:
251178
AF XY:
0.000103
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000705
AC:
103
AN:
1461290
Hom.:
0
Cov.:
32
AF XY:
0.0000660
AC XY:
48
AN XY:
726950
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86224
European-Finnish (FIN)
AF:
0.0000936
AC:
5
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5530
European-Non Finnish (NFE)
AF:
0.0000801
AC:
89
AN:
1111766
Other (OTH)
AF:
0.000116
AC:
7
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
7
15
22
30
37
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68050
Other (OTH)
AF:
0.000478
AC:
1
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.538
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000166
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:3
Apr 19, 2021
Clinical Genetics Laboratory, Region Ostergotland
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PVS1, PS4, PP5, BP5 -

Aug 01, 2013
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Feb 07, 2024
Myriad Genetics, Inc.
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:3
May 31, 2015
Clinical Genetics and Genomics, Karolinska University Hospital
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 29, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32255556, 28500238, 27899191, 24694336, 27159395, 29978154, 28384794, 30877234, 33726816, 32570879, 23750034) -

Jan 31, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This nonsense variant causes the premature termination of SDHA protein synthesis. The frequency of this variant in the general population, 0.00065 (17/26134 chromosomes in Swedish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. However, in the published literature, this variant is reported as being associated with reduced penetrance of developing cancer (PMID: 29978154 (2018)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32570879 (2020)), pancreatic ductal adenocarcinoma (PDAC) (PMID: 32255556 (2020)), and hereditary paraganglioma-pheochromocytoma (PGL-PCC) (PMIDs: 30877234 (2019), 24694336 (2014), 23750034 (2013)). Based on the available information, this variant is classified as pathogenic. -

Dilated cardiomyopathy 1GG Pathogenic:1
Oct 16, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg75*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (rs781764920, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with paraganglioma and/or pheochromocytoma (PMID: 23750034, 24694336). ClinVar contains an entry for this variant (Variation ID: 209127). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1
Jun 19, 2024
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 3 of the SDHA gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation was reported in a woman with a paraganglioma diagnosed at age 20 (Welander J et al. J. Clin. Endocrinol. Metab., 2013 Aug;98:E1379-80) and in a male diagnosed with pheochromocytoma at 47 (Welander J et al. J Clin Endocrinol Metab, 2014 Jul;99:E1352-60). This mutation has also been identified in individuals with spindle cell breast cancer and pancreatic cancer (Sprissler R et al. Cancers (Basel), 2020 Jun;12; Cremin C et al. Cancer Med, 2020 06;9:4004-4013). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Jan 04, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.85
D
PhyloP100
2.1
Vest4
0.93
GERP RS
4.7
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs781764920; hg19: chr5-224547; COSMIC: COSV53774237; COSMIC: COSV53774237; API