VCV002562379.4 - ClinVar

NM_004168.4(SDHA):c.3G>A (p.Met1Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004168.4(SDHA):c.3G>A (p.Met1Ile)

Variation ID: 2562379 Accession: VCV002562379.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p15.33 5: 218358 (GRCh38) [ NCBI UCSC ] 5: 218473 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 8, 2023	May 1, 2024	Feb 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004168.4:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004159.2:p.Met1Ile	missense initiator codon variant
NM_001294332.2:c.3G>A	NP_001281261.1:p.Met1Ile	missense initiator codon variant
NM_001330758.2:c.3G>A	NP_001317687.1:p.Met1Ile	missense initiator codon variant
NC_000005.10:g.218358G>A
NC_000005.9:g.218473G>A
NG_012339.1:g.5118G>A
NG_033064.1:g.4825C>T
NG_104118.1:g.129G>A
NG_104118.2:g.328G>A
LRG_315:g.5118G>A
LRG_315t1:c.3G>A	LRG_315p1:p.Met1Ile

... more HGVS ... less HGVS

Protein change

M1I

Other names

Canonical SPDI

NC_000005.10:218357:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SDHA		-	-	GRCh38 GRCh37	2733	2892

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 22, 2023	RCV003310439.2
Mitochondrial complex II deficiency, nuclear type 1 Paragangliomas 5	Pathogenic (1)	criteria provided, single submitter	Jan 2, 2024	RCV003777136.2
Paragangliomas 5	Pathogenic (1)	criteria provided, single submitter	Feb 6, 2024	RCV004330175.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Paragangliomas 5 Mitochondrial complex II deficiency, nuclear type 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004583082.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 24096523‚ 26642834‚ 26722403‚ 28384794 Comment: 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 … (more) 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 autosomal recessive complex II deficiency, gastrointestinal stromal tumor and renal cell carcinoma, and/or paraganglioma (PMID: 24096523, 26642834, 26722403, 28384794; Invitae). ClinVar contains an entry for this variant (Variation ID: 2562379). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 06, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Paragangliomas 5 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004933733.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 35014173‚ 28384794‚ 10746566‚ 26722403‚ 32971818 Comment: 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. … (more) 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: 35014173, 28384794, 10746566, 26722403, 32971818]. (less)
Pathogenic (Mar 22, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004001105.3 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the SDHA gene and results from a G to A … (more) The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the SDHA gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). 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. (less)

Comment:

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 autosomal recessive complex II deficiency, gastrointestinal stromal tumor and renal cell carcinoma, and/or paraganglioma (PMID: 24096523, 26642834, 26722403, 28384794; Invitae). ClinVar contains an entry for this variant (Variation ID: 2562379). For these reasons, this variant has been classified as Pathogenic.

Comment:

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: 35014173, 28384794, 10746566, 26722403, 32971818].

Comment:

The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the SDHA gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees.	Yang Z	American journal of medical genetics. Part A	2022	PMID: 35014173
Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas.	Snezhkina AV	International journal of molecular sciences	2020	PMID: 32971818
Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.	Bausch B	JAMA oncology	2017	PMID: 28384794
Magnetic resonance imaging spectrum of succinate dehydrogenase-related infantile leukoencephalopathy.	Helman G	Annals of neurology	2016	PMID: 26642834
A novel germline mutation in SDHA identified in a rare case of gastrointestinal stromal tumor complicated with renal cell carcinoma.	Jiang Q	International journal of clinical and experimental pathology	2015	PMID: 26722403
Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis.	Papathomas TG	European journal of endocrinology	2013	PMID: 24096523
Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome.	Parfait B	Human genetics	2000	PMID: 10746566

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_004168.4(SDHA):c.3G>A (p.Met1Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...