VCV000037245.48 - ClinVar

NM_006205.3(PDE6H):c.35C>G (p.Ser12Ter)

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.

(10)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006205.3(PDE6H):c.35C>G (p.Ser12Ter)

Variation ID: 37245 Accession: VCV000037245.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p12.3 12: 14978047 (GRCh38) [ NCBI UCSC ] 12: 15130981 (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 4, 2013	Oct 20, 2024	Jan 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006205.3:c.35C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006196.1:p.Ser12Ter	nonsense
NC_000012.12:g.14978047C>G
NC_000012.11:g.15130981C>G
NG_016859.1:g.10026C>G

Protein change

S12*

Other names

Canonical SPDI

NC_000012.12:14978046:C:G

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00008

The Genome Aggregation Database (gnomAD) 0.00012

Links

OMIM: 601190.0002 dbSNP: rs200311463 ClinGen: CA130125 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.
PDE6H		-	-	GRCh38 GRCh37	65	104

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.
Achromatopsia 6	Pathogenic (1)	no assertion criteria provided	Sep 7, 2012	RCV000030807.5
Retinal cone dystrophy 3A	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	May 23, 2022	RCV000055928.14
PDE6H-related disorder	Likely pathogenic (1)	criteria provided, single submitter	Aug 23, 2018	RCV000779093.5
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 12, 2024	RCV001092385.29

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.
Likely pathogenic (Aug 23, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	PDE6H-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915582.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (2) PubMed: 22901948‚ 27472364 Comment: The PDE6H c.35C>G (p.Ser12Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Ser12Ter variant has … (more) The PDE6H c.35C>G (p.Ser12Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Ser12Ter variant has been reported in two studies and is found in a homozygous state in five probands from three families including two sibling pairs (Kohl et al. 2012; Pedurupillay et al. 2016). Three of the probands are diagnosed with incomplete achromatopsia and two with cone dystrophy. The unaffected parents of the siblings were confirmed heterozygotes for the p.Ser12Ter variant. The p.Ser12Ter variant was absent from 180 control subjects and is reported at a frequency of 0.000166 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants and evidence from the literature, the p.Ser12Ter variant is classified as likely pathogenic for PDE6H-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (May 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal cone dystrophy 3A Affected status: yes Allele origin: germline	Institute of Human Genetics, Heidelberg University Accession: SCV002556342.1 First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022	Sex: male
Pathogenic (Jan 12, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002227721.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 22901948‚ 27472364 Comment: This sequence change creates a premature translational stop signal (p.Ser12) in the PDE6H gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ser12) in the PDE6H gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDE6H are known to be pathogenic (PMID: 22901948, 27472364). This variant is present in population databases (rs200311463, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with achromatopsia (PMID: 22901948, 27472364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37245). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Dec 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal cone dystrophy 3A Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369732.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to … (more) This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5. (less)
Pathogenic (Nov 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248872.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Oct 27, 2015)	no assertion criteria provided Method: research	Retinal cone dystrophy 3A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000256082.1 First in ClinVar: Oct 02, 2013 Last updated: Oct 02, 2013	Clinical Features: Incomplete achromatopsia (present) Family history: yes Sex: male Ethnicity/Population group: Pakistan Tissue: leucocytes Segregation observed: yes Method: Whole exome sequencing was used to identify the variant and Sanger sequencing to verify segregation.
Pathogenic (Sep 07, 2012)	no assertion criteria provided Method: literature only	ACHROMATOPSIA 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000053478.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 01, 2021	Publications: PubMed (1) PubMed: 22901948 Comment on evidence: In a Dutch man and a Belgian brother and sister with incomplete achromatopsia (ACHM6; see 610024), Kohl et al. (2012) identified homozygosity for a 35C-G … (more) In a Dutch man and a Belgian brother and sister with incomplete achromatopsia (ACHM6; see 610024), Kohl et al. (2012) identified homozygosity for a 35C-G transversion in exon 2 of the PDE6H gene, resulting in a ser12-to-ter (S12X) substitution predicted to result in a truncated protein of only 11 amino acids. The Belgian parents were heterozygous for the mutation, which was not found in any database query. Kohl et al. (2012) noted that the protein would likely represent a functional null allele, as it would lack all conserved domains relevant for transducin binding and inhibition of the catalytic activity of PDE; however, it was predicted to undergo nonsense-mediated decay. Haplotype analysis identified a common 301-kb haplotype flanked by rs111596034 (D12S2210) and rs2430621, suggesting that the S12X mutation resulted from a common ancestral mutational event in the 2 families. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957650.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971195.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: literature only	Retinal cone dystrophy 3A Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086940.3 First in ClinVar: Oct 02, 2013 Last updated: Apr 23, 2023	Publications: PubMed (2) PubMed: 22901948‚ 27472364 Bookshelf: NBK1418 Bookshelf: NBK1418

Comment:

The PDE6H c.35C>G (p.Ser12Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Ser12Ter variant has been reported in two studies and is found in a homozygous state in five probands from three families including two sibling pairs (Kohl et al. 2012; Pedurupillay et al. 2016). Three of the probands are diagnosed with incomplete achromatopsia and two with cone dystrophy. The unaffected parents of the siblings were confirmed heterozygotes for the p.Ser12Ter variant. The p.Ser12Ter variant was absent from 180 control subjects and is reported at a frequency of 0.000166 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants and evidence from the literature, the p.Ser12Ter variant is classified as likely pathogenic for PDE6H-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change creates a premature translational stop signal (p.Ser12*) in the PDE6H gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDE6H are known to be pathogenic (PMID: 22901948, 27472364). This variant is present in population databases (rs200311463, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with achromatopsia (PMID: 22901948, 27472364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37245). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5.

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
Achromatopsia.	Adam MP	-	2018	PMID: 20301591
Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan.	Pedurupillay CR	Genes	2016	PMID: 27472364
A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia.	Kohl S	American journal of human genetics	2012	PMID: 22901948

Text-mined citations for rs200311463 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_006205.3(PDE6H):c.35C>G (p.Ser12Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200311463 ...