VCV000014834.10 - ClinVar

NM_000883.4(IMPDH1):c.931G>A (p.Asp311Asn)

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.

(6)

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/Likely 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_000883.4(IMPDH1):c.931G>A (p.Asp311Asn)

Variation ID: 14834 Accession: VCV000014834.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q32.1 7: 128398557 (GRCh38) [ NCBI UCSC ] 7: 128038611 (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	Mar 10, 2024	Dec 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000883.4:c.931G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000874.2:p.Asp311Asn	missense
NM_001102605.2:c.901G>A	NP_001096075.1:p.Asp301Asn	missense
NM_001142573.2:c.676G>A	NP_001136045.1:p.Asp226Asn	missense
NM_001142574.2:c.661G>A	NP_001136046.1:p.Asp221Asn	missense
NM_001142575.2:c.601G>A	NP_001136047.1:p.Asp201Asn	missense
NM_001142576.2:c.832G>A	NP_001136048.1:p.Asp278Asn	missense
NM_001304521.2:c.724G>A	NP_001291450.1:p.Asp242Asn	missense
NM_183243.3:c.823G>A	NP_899066.1:p.Asp275Asn	missense
NC_000007.14:g.128398557C>T
NC_000007.13:g.128038611C>T
NG_009194.1:g.16426G>A

... more HGVS ... less HGVS

Protein change

D226N, D201N, D221N, D275N, D278N, D301N, D311N, D242N

Other names

Canonical SPDI

NC_000007.14:128398556: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA257369 OMIM: 146690.0001 dbSNP: rs121912550 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.
IMPDH1		-	-	GRCh38 GRCh37	553	637

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.
Retinitis pigmentosa 10	Pathogenic (2)	criteria provided, single submitter	Apr 8, 2021	RCV000015959.26
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 11, 2023	RCV000255540.10
Retinal dystrophy	Likely pathogenic (1)	criteria provided, single submitter	Oct 1, 2023	RCV003887871.1

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 (Nov 01, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322376.7 First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016	Comment: Published functional studies demonstrate a damaging effect with impaired protein folding (Wang et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, … (more) Published functional studies demonstrate a damaging effect with impaired protein folding (Wang et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15851576, 28945494, 21791244, 16671097, 25439607, 11875050, 29847639, 31126147, 32821486) (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447665.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 10 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573294.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Comment: The IMPDH1 c.931G>A variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we … (more) The IMPDH1 c.931G>A variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Dec 11, 2023)	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: SCV001206486.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 11875050‚ 28945494‚ 15882147‚ 21791244 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 311 of the IMPDH1 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 311 of the IMPDH1 protein (p.Asp311Asn). This variant is present in population databases (rs121912550, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 11875050, 28945494). It has also been observed to segregate with disease in related individuals. This variant is also known as Asp226Asn. ClinVar contains an entry for this variant (Variation ID: 14834). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IMPDH1 function (PMID: 15882147, 21791244). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004704785.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Pathogenic (Jun 01, 2006)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 10 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036226.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (3) PubMed: 11875050‚ 15851576‚ 16671097 Comment on evidence: Among 3 families with autosomal dominant retinitis pigmentosa linked to 7q (RP10; 180105), Bowne et al. (2002) identified a G-to-A transition at codon 226 of … (more) Among 3 families with autosomal dominant retinitis pigmentosa linked to 7q (RP10; 180105), Bowne et al. (2002) identified a G-to-A transition at codon 226 of the IMPDH1 gene, substituting an asparagine for an aspartic acid (D226N). Asp226 is highly evolutionarily conserved among IMPDH genes, suggesting that this mutation may be highly deleterious. Wada et al. (2005) identified the D226N mutation in 6 of 183 unrelated patients with autosomal dominant RP. Taking into account the 135 patients excluded from the study because of previously identified mutations in other dominant RP genes, Wada et al. (2005) estimated that IMPDH1 mutations account for approximately 2% of cases of dominant RP in North America. Based on a comparison of electroretinogram (ERG) amplitudes among carriers of the IMPDH1 D226N mutation, the RP1 mutation R677X (603937.0001), the rhodopsin mutation P23H (180380.0001), and the rhodopsin mutation P347L (180380.0002), Wada et al. (2005) concluded that D226N, the most frequent mutation, appeared to cause at least as much loss of rod function as cone function, and that patients with this form of RP retained, on average, 2 to 5 times more ERG amplitude per unit of remaining visual area than patients with the 3 other forms of dominant RP. Bischof et al. (2006) identified a processed pseudogene for IMPDH1 carrying the 676G-A transition that produces the D226N substitution. The authors suggested that this case may represent a novel gene conversion event involving a processed pseudogene. (less)

Comment:

Published functional studies demonstrate a damaging effect with impaired protein folding (Wang et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15851576, 28945494, 21791244, 16671097, 25439607, 11875050, 29847639, 31126147, 32821486)

Comment:

The IMPDH1 c.931G>A variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic.

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 311 of the IMPDH1 protein (p.Asp311Asn). This variant is present in population databases (rs121912550, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 11875050, 28945494). It has also been observed to segregate with disease in related individuals. This variant is also known as Asp226Asn. ClinVar contains an entry for this variant (Variation ID: 14834). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IMPDH1 function (PMID: 15882147, 21791244). For these reasons, this variant has been classified as 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
Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent.	Villanueva A	Ophthalmic genetics	2018	PMID: 28945494
Molecular recruitment as a basis for negative dominant inheritance? propagation of misfolding in oligomers of IMPDH1, the mutated enzyme in the RP10 form of retinitis pigmentosa.	Wang XT	Biochimica et biophysica acta	2011	PMID: 21791244
Genome-wide identification of pseudogenes capable of disease-causing gene conversion.	Bischof JM	Human mutation	2006	PMID: 16671097
Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid binding.	Mortimer SE	The Biochemical journal	2005	PMID: 15882147
Screen of the IMPDH1 gene among patients with dominant retinitis pigmentosa and clinical features associated with the most common mutation, Asp226Asn.	Wada Y	Investigative ophthalmology & visual science	2005	PMID: 15851576
Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa.	Bowne SJ	Human molecular genetics	2002	PMID: 11875050

Text-mined citations for rs121912550 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000883.4(IMPDH1):c.931G>A (p.Asp311Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912550 ...