VCV003236684.4 - ClinVar

NM_001104631.2(PDE4D):c.665T>C (p.Ile222Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

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

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001104631.2(PDE4D):c.665T>C (p.Ile222Thr)

Variation ID: 3236684 Accession: VCV003236684.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q11.2 5: 59193519 (GRCh38) [ NCBI UCSC ] 5: 58489345 (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	May 27, 2024	Apr 13, 2025	Sep 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001104631.2:c.665T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001098101.1:p.Ile222Thr	missense
NM_001165899.2:c.482T>C	NP_001159371.1:p.Ile161Thr	missense
NM_001197218.2:c.473T>C	NP_001184147.1:p.Ile158Thr	missense
NM_001197219.2:c.299T>C	NP_001184148.1:p.Ile100Thr	missense
NM_001197220.2:c.275T>C	NP_001184149.1:p.Ile92Thr	missense
NM_001349241.2:c.452T>C	NP_001336170.1:p.Ile151Thr	missense
NM_001349242.2:c.335T>C	NP_001336171.1:p.Ile112Thr	missense
NM_001349243.2:c.-30T>C		5 prime UTR
NM_001364599.1:c.482T>C	NP_001351528.1:p.Ile161Thr	missense
NM_001364600.2:c.482T>C	NP_001351529.1:p.Ile161Thr	missense
NM_001364602.2:c.473T>C	NP_001351531.1:p.Ile158Thr	missense
NM_001364603.1:c.-286T>C		5 prime UTR
NM_001364604.1:c.-30T>C		5 prime UTR
NM_006203.5:c.257T>C	NP_006194.2:p.Ile86Thr	missense
NC_000005.10:g.59193519A>G
NC_000005.9:g.58489345A>G
NG_027957.2:g.1335811T>C

... more HGVS ... less HGVS

Protein change

I100T, I112T, I151T, I158T, I161T, I222T, I86T, I92T

Other names

Canonical SPDI

NC_000005.10:59193518:A: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.

Links

ClinGen: CA359930507 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.
PDE4D		No evidence available	No evidence available	GRCh38 GRCh37	595	624

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.
Acrodysostosis 2 with or without hormone resistance	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Sep 3, 2024	RCV004556144.5

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 (Sep 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrodysostosis 2 with or without hormone resistance (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen Accession: SCV005044907.3 First in ClinVar: May 26, 2024 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 33858404 Comment: The variant is not listed in control databases (gnomAD). ClinVar contains no entry for this variant. Bioninformatic prediction tools predict a deleterious effect (CADD Phred … (more) The variant is not listed in control databases (gnomAD). ClinVar contains no entry for this variant. Bioninformatic prediction tools predict a deleterious effect (CADD Phred 26.7, REVEL 0.749). The Variant segregates within two affected individuals in one family. The variant is located within the regulatory domain of the PDE4D protein (UCR1 region), where other (likely) pathogenic variants have been desribed before (PMID: 33858404).The variant is classified as likely pathogenic. (less) Clinical Features: Midface retrusion (present) , Short stature (present) , Cognitive impairment (present) , Brachydactyly (present) Zygosity: Single Heterozygote Sex: female
Uncertain significance (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrodysostosis 2 with or without hormone resistance Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005416394.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PP3+PM6_Supporting+PP2

Comment:

The variant is not listed in control databases (gnomAD). ClinVar contains no entry for this variant. Bioninformatic prediction tools predict a deleterious effect (CADD Phred 26.7, REVEL 0.749). The Variant segregates within two affected individuals in one family. The variant is located within the regulatory domain of the PDE4D protein (UCR1 region), where other (likely) pathogenic variants have been desribed before (PMID: 33858404).The variant is classified as likely pathogenic.

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
A novel variant in the PDE4D gene is the cause of Acrodysostosis type 2 in a Lithuanian patient: a case report.	Petraitytė G	BMC endocrine disorders	2021	PMID: 33858404

Text-mined citations for this variant ...

Record last updated Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_001104631.2(PDE4D):c.665T>C (p.Ile222Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...