VCV000903472.16 - ClinVar

NM_025132.4(WDR19):c.3683C>G (p.Ala1228Gly)

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.

(7)

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_025132.4(WDR19):c.3683C>G (p.Ala1228Gly)

Variation ID: 903472 Accession: VCV000903472.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p14 4: 39274925 (GRCh38) [ NCBI UCSC ] 4: 39276545 (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 31, 2020	May 1, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025132.4:c.3683C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079408.3:p.Ala1228Gly	missense
NM_001317924.2:c.3203C>G	NP_001304853.1:p.Ala1068Gly	missense
NC_000004.12:g.39274925C>G
NC_000004.11:g.39276545C>G
NG_031813.1:g.97522C>G

... more HGVS ... less HGVS

Protein change

A1068G, A1228G

Other names

Canonical SPDI

NC_000004.12:39274924: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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Exome Aggregation Consortium (ExAC) 0.00009

The Genome Aggregation Database (gnomAD) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00013

Trans-Omics for Precision Medicine (TOPMed) 0.00015

Links

dbSNP: rs201051877 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.
WDR19		-	-	GRCh38 GRCh37	1075	1103

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.
Cranioectodermal dysplasia 4	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001150824.4
Asphyxiating thoracic dystrophy 5	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001150825.4
Asphyxiating thoracic dystrophy 5 Senior-Loken syndrome 8	Uncertain significance (1)	criteria provided, single submitter	Jan 30, 2024	RCV001202819.6
Connective tissue disorder	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2019	RCV002276645.3
Asphyxiating thoracic dystrophy 5 Cranioectodermal dysplasia 4 Nephronophthisis 13 Senior-Loken syndrome 8 Spermatogenic failure 72	Uncertain significance (1)	criteria provided, single submitter	Mar 16, 2022	RCV002497570.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Feb 16, 2023	RCV003163337.2
WDR19-related disorder	Uncertain significance (1)	criteria provided, single submitter	Apr 30, 2023	RCV004538377.1

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.
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cranioectodermal dysplasia 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001311916.1 First in ClinVar: May 31, 2020 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Asphyxiating thoracic dystrophy 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001311917.1 First in ClinVar: May 31, 2020 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Senior-Loken syndrome 8 Asphyxiating thoracic dystrophy 5 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: SCV001373948.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Comment: This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1228 of the WDR19 protein (p.Ala1228Gly). … (more) This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1228 of the WDR19 protein (p.Ala1228Gly). This variant is present in population databases (rs201051877, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WDR19-related conditions. ClinVar contains an entry for this variant (Variation ID: 903472). 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) performed at Invitae indicates that this missense variant is not expected to disrupt WDR19 protein function with a negative predictive value of 80%. 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 (Aug 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002567173.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Uncertain significance (Mar 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Asphyxiating thoracic dystrophy 5 Nephronophthisis 13 Cranioectodermal dysplasia 4 Senior-Loken syndrome 8 Spermatogenic failure 72 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002804992.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Apr 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	WDR19-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114471.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The WDR19 c.3683C>G variant is predicted to result in the amino acid substitution p.Ala1228Gly. To our knowledge, this variant has not been reported in the … (more) The WDR19 c.3683C>G variant is predicted to result in the amino acid substitution p.Ala1228Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-39276545-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Feb 16, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003868708.2 First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024	Comment: The c.3683C>G (p.A1228G) alteration is located in exon 33 (coding exon 33) of the WDR19 gene. This alteration results from a C to G substitution … (more) The c.3683C>G (p.A1228G) alteration is located in exon 33 (coding exon 33) of the WDR19 gene. This alteration results from a C to G substitution at nucleotide position 3683, causing the alanine (A) at amino acid position 1228 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1228 of the WDR19 protein (p.Ala1228Gly). This variant is present in population databases (rs201051877, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WDR19-related conditions. ClinVar contains an entry for this variant (Variation ID: 903472). 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) performed at Invitae indicates that this missense variant is not expected to disrupt WDR19 protein function with a negative predictive value of 80%. 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 WDR19 c.3683C>G variant is predicted to result in the amino acid substitution p.Ala1228Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-39276545-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

The c.3683C>G (p.A1228G) alteration is located in exon 33 (coding exon 33) of the WDR19 gene. This alteration results from a C to G substitution at nucleotide position 3683, causing the alanine (A) at amino acid position 1228 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs201051877 ...

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_025132.4(WDR19):c.3683C>G (p.Ala1228Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201051877 ...