chr1-161314406-A-T

Variant names:

• chr1-161314406-A-T
• rs755235380
• NM_003001.5:c.1A>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001407119.1(SDHC):​c.-560A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHC NM_001407119.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.48

Genes affected

SDHC (HGNC:10682): (succinate dehydrogenase complex subunit C) This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-161314406-A-T is Pathogenic according to our data. Variant chr1-161314406-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 653751.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
SDHC	NM_003001.5	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727238

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2024

This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with SDHC-related conditions (PMID: 11062460, 16249420, 19351833, 19454582, 22351710, 22517554, 23282968, 29386252). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 653751). For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 12, 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: 30201732, 30877234, 16249420, 11062460, 25720320]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the SDHC gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was reported in multiple individuals with features consistent with SDHC-related paraganglioma-pheochromocytoma syndrome (Andrews KA et al. J Med Genet, 2018 Jun;55:384-394; Williams et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PROVEAN	Benign	-0.70	N;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Benign	0.090	T;D;D;D;D
Polyphen		0.0	B;B;B;P;P
Vest4		0.78
MutPred		0.93		Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);Gain of stability (P = 0.0265);
MVP		0.90
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs755235380; hg19: chr1-161284196; COSMIC: COSV104631990; COSMIC: COSV104631990;