VCV000412376.26 - ClinVar

NM_004168.4(SDHA):c.1724C>T (p.Ala575Val)

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.

(8)

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.

Uncertain significance

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.1724C>T (p.Ala575Val)

Variation ID: 412376 Accession: VCV000412376.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p15.33 5: 251398 (GRCh38) [ NCBI UCSC ] 5: 251513 (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	Apr 29, 2017	Sep 29, 2024	May 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004168.4:c.1724C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004159.2:p.Ala575Val	missense
NM_001294332.2:c.1580C>T	NP_001281261.1:p.Ala527Val	missense
NM_001330758.2:c.1552-2995C>T		intron variant
NC_000005.10:g.251398C>T
NC_000005.9:g.251513C>T
NG_012339.1:g.38158C>T
LRG_315:g.38158C>T
LRG_315t1:c.1724C>T	LRG_315p1:p.Ala575Val

... more HGVS ... less HGVS

Protein change

A575V, A527V

Other names

Canonical SPDI

NC_000005.10:251397:C:T

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.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA3173339 dbSNP: rs750327309 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	2739	2898

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.
Mitochondrial complex II deficiency, nuclear type 1 Paragangliomas 5	Uncertain significance (1)	criteria provided, single submitter	Jan 26, 2024	RCV000467983.13
not provided	Uncertain significance (1)	criteria provided, single submitter	May 7, 2024	RCV000487393.7
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 18, 2022	RCV000572994.9
Paragangliomas 5	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 20, 2023	RCV000663257.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV002268094.6
Dilated cardiomyopathy 1GG	Uncertain significance (1)	criteria provided, single submitter	Mar 27, 2024	RCV003476132.2

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.
Uncertain significance (May 08, 2018)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Paragangliomas 5 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000786484.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018
Uncertain significance (Nov 25, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002527728.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The SDHA c.1724C>T (p.A575V) variant has been reported in one individual with five different primary tumors (PMID: 34711244). However, this patient also has other risk … (more) The SDHA c.1724C>T (p.A575V) variant has been reported in one individual with five different primary tumors (PMID: 34711244). However, this patient also has other risk alleles detected in CHEK2 and HOXB13 genes. It was observed in 3/21642 chromosomes of the European Finnish subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 412376). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (1) PubMed: 34711244
Uncertain significance (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550449.4 First in ClinVar: Jul 28, 2022 Last updated: Aug 18, 2023
Uncertain significance (Jan 26, 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: SCV000553894.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 575 of the SDHA protein (p.Ala575Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 575 of the SDHA protein (p.Ala575Val). This variant is present in population databases (rs750327309, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 412376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 18, 2022)	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: SCV000674974.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: The p.A575V variant (also known as c.1724C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide … (more) The p.A575V variant (also known as c.1724C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1724. The alanine at codon 575 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (May 07, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000570527.9 First in ClinVar: Apr 29, 2017 Last updated: Sep 29, 2024	Comment: Observed in a patient with multiple primary tumors who also harbored pathogenic variants in CHEK2 and HOXB13 (PMID: 34711244); Not observed at significant frequency in … (more) Observed in a patient with multiple primary tumors who also harbored pathogenic variants in CHEK2 and HOXB13 (PMID: 34711244); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 34711244) (less)
Uncertain significance (Apr 20, 2023)	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: SCV004018574.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1GG Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202386.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 575 of the SDHA protein (p.Ala575Val). This variant is present in population databases (rs750327309, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 412376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.A575V variant (also known as c.1724C>T), located in coding exon 13 of the SDHA gene, results from a C to T substitution at nucleotide position 1724. The alanine at codon 575 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Observed in a patient with multiple primary tumors who also harbored pathogenic variants in CHEK2 and HOXB13 (PMID: 34711244); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 34711244)

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
Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis.	Wallander K	Hereditary cancer in clinical practice	2021	PMID: 34711244

Text-mined citations for rs750327309 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_004168.4(SDHA):c.1724C>T (p.Ala575Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750327309 ...