This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ClinVar Genomic variation as it relates to human health
NM_031220.4(PITPNM3):c.1878G>C (p.Gln626His)
Germline
Classification
Help
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)
Help
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
Likely pathogenic(1); Uncertain significance(2); Benign(1); Likely benign(3)
Likely pathogenic(1); Uncertain significance(2); Benign(1); Likely benign(3)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_031220.4(PITPNM3):c.1878G>C (p.Gln626His)
Variation ID: 1994 Accession: VCV000001994.48
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 6468237 (GRCh38) [ NCBI UCSC ] 17: 6371557 (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 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_031220.4:c.1878G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_112497.2:p.Gln626His missense NM_001165966.2:c.1770G>C NP_001159438.1:p.Gln590His missense NC_000017.11:g.6468237C>G NC_000017.10:g.6371557C>G NG_016020.1:g.93321G>C Q9BZ71:p.Gln626His - Protein change
- Q626H, Q590H
- Other names
- -
- Canonical SPDI
- NC_000017.11:6468236:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
0.00140 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00140
Exome Aggregation Consortium (ExAC) 0.00144
The Genome Aggregation Database (gnomAD), exomes 0.00160
1000 Genomes Project 30x 0.00172
The Genome Aggregation Database (gnomAD) 0.00212
Trans-Omics for Precision Medicine (TOPMed) 0.00212
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PITPNM3 | - | - |
GRCh38 GRCh37 |
878 | 914 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
May 21, 2020 | RCV000002071.21 | |
| Likely benign (1) |
criteria provided, single submitter
|
Oct 19, 2017 | RCV000153697.13 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 25, 2024 | RCV000512878.41 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Apr 1, 2018 | RCV000787861.9 | |
|
PITPNM3-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Feb 14, 2020 | RCV003934792.2 |
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
(Feb 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000203255.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Likely benign
(Oct 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000730655.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Uncertain significance
(Apr 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cone-rod dystrophy 5
Affected status: unknown
Allele origin:
paternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782437.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cone-rod dystrophy 5
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000405823.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
|
Likely benign
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001099581.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
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Likely benign
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cone-rod dystrophy 5
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769125.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
A heterozygous missense variant was identified, NM_031220.3(PITPNM3):c.1878G>C in exon 14 of the PITPNM3 gene. This substitution is predicted to create a minor amino acid change … (more)
A heterozygous missense variant was identified, NM_031220.3(PITPNM3):c.1878G>C in exon 14 of the PITPNM3 gene. This substitution is predicted to create a minor amino acid change from a glutamine to a histidine at position 626 of the protein; NP_112497.2(PITPNM3):p.(Gln626His). The glutamine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.16% (455 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.31%. This variant has been previously reported with conflicting interpretations of pathogenicity in patients with cone-rod dystrophy (ClinVar, Reinis A. et al. (2013), Zhao, L. et al (2015), Khan, K. et al (2017), Jespersgaard, C. et al. (2019)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN. (less)
|
|
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Likely pathogenic
(Apr 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608801.31
First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926877.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
|
Likely benign
(Feb 14, 2020)
|
no assertion criteria provided
Method: clinical testing
|
PITPNM3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004752112.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
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Pathogenic
(Jun 01, 2007)
|
Flagged submission
flagged submission
Method: literature only
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
CONE-ROD DYSTROPHY 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022229.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of 2 multigenerational Swedish families with cone dystrophy (CORD5; 600977), 1 of which was a family previously reported by Balciuniene et al. … (more)
In affected members of 2 multigenerational Swedish families with cone dystrophy (CORD5; 600977), 1 of which was a family previously reported by Balciuniene et al. (1995), Kohn et al. (2007) identified heterozygosity for a 1878G-C transversion in exon 14 of the PITPNM3 gene, resulting in a gln626-to-his (Q626H) substitution at a conserved residue. The mutation was not found in 322 ethnically matched control chromosomes or in 140 individuals with autosomal dominant or recessive retinitis pigmentosa (see 180100). (less)
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
A heterozygous missense variant was identified, NM_031220.3(PITPNM3):c.1878G>C in exon 14 of the PITPNM3 gene. This substitution is predicted to create a minor amino acid change from a glutamine to a histidine at position 626 of the protein; NP_112497.2(PITPNM3):p.(Gln626His). The glutamine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.16% (455 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.31%. This variant has been previously reported with conflicting interpretations of pathogenicity in patients with cone-rod dystrophy (ClinVar, Reinis A. et al. (2013), Zhao, L. et al (2015), Khan, K. et al (2017), Jespersgaard, C. et al. (2019)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
A heterozygous missense variant was identified, NM_031220.3(PITPNM3):c.1878G>C in exon 14 of the PITPNM3 gene. This substitution is predicted to create a minor amino acid change from a glutamine to a histidine at position 626 of the protein; NP_112497.2(PITPNM3):p.(Gln626His). The glutamine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.16% (455 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.31%. This variant has been previously reported with conflicting interpretations of pathogenicity in patients with cone-rod dystrophy (ClinVar, Reinis A. et al. (2013), Zhao, L. et al (2015), Khan, K. et al (2017), Jespersgaard, C. et al. (2019)). Based on information available at the time of curation, this variant has been classified as LIKELY BENIGN.
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
| Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service. | Khan KN | Clinical genetics | 2017 | PMID: 27160483 |
| Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. | Zhao L | Human genetics | 2015 | PMID: 25472526 |
| Ocular phenotype of CORD5, an autosomal dominant retinal dystrophy associated with PITPNM3 p.Q626H mutation. | Reinis A | Acta ophthalmologica | 2013 | PMID: 22405330 |
| Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families. | Köhn L | European journal of human genetics : EJHG | 2007 | PMID: 17377520 |
| A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13. | Balciuniene J | Genomics | 1995 | PMID: 8586428 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PITPNM3 | - | - | - | - |
Text-mined citations for rs76024428 ...
HelpThese 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 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.