VCV001705979.3 - ClinVar

NM_022841.7(RFX7):c.3082C>T (p.Pro1028Ser)

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.

(3)

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_022841.7(RFX7):c.3082C>T (p.Pro1028Ser)

Variation ID: 1705979 Accession: VCV001705979.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.3 15: 56094646 (GRCh38) [ NCBI UCSC ] 15: 56386844 (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	Mar 26, 2023	Jul 23, 2024	Nov 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_022841.7:c.3082C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_073752.6:p.Pro1028Ser	missense
NM_001368073.2:c.2791C>T	NP_001355002.1:p.Pro931Ser	missense
NM_001368074.1:c.2791C>T	NP_001355003.1:p.Pro931Ser	missense
NM_001370554.1:c.2791C>T	NP_001357483.1:p.Pro931Ser	missense
NM_001370561.1:c.3082C>T	NP_001357490.1:p.Pro1028Ser	missense
NM_022841.5:c.3082C>T
NC_000015.10:g.56094646G>A
NC_000015.9:g.56386844G>A

... more HGVS ... less HGVS

Protein change

P1028S, P931S

Other names

Canonical SPDI

NC_000015.10:56094645:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

probably has functional consequence

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

OMIM: 612660.0005 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.
RFX7		-	-	GRCh38 GRCh37	161	179

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.
See cases	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003153252.2
Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities	Pathogenic (1)	no assertion criteria provided	Apr 19, 2023	RCV003223346.1
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 22, 2022	RCV004591865.1

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Medical Genetics Clinic, University of Alberta Accession: SCV002573589.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (2) PubMed: 33658631‚ 33584783 Comment: This heterozygous missense variant in RFX7 c. 3082C>T, p.(Pro1028Ser) (NM_022841.7) occurred de novo and was predicted to be likely pathogenic. The patient presented with developmental … (more) This heterozygous missense variant in RFX7 c. 3082C>T, p.(Pro1028Ser) (NM_022841.7) occurred de novo and was predicted to be likely pathogenic. The patient presented with developmental delay, severe failure to thrive, and progressive white matter volume loss. (less) Clinical Features: Neurodevelopmental delay (present) , Global developmental delay (present) , Global developmental delay (present) , Failure to thrive (present) Age: 0-9 years Sex: male Method: Whole exome sequencing was performed in a CAP and ISO accredited laboratory. Total genomic DNA was extracted, exonic and selected non-coding regions were captured with the IDT Gen Exome Research Panel with custom-designed capture probes, followed by paired-end sequencing (150 by 150 bases) using the Illumina sequencing system (NovaSeq). Sequencing-derived raw image files were processed using base-calling software (Illumina) and the sequence data were transformed into FASTQ format. Clean sequence reads were mapped to the human reference genome (GRCh37/hg19). Burrows–Wheeler Aligner (BWA-MEM) software was used for read alignment. Duplicate read marking, local realignment around indels, base quality score recalibration, and variant calling were performed using GATK algorithms (Sentieon). Variants were annotated using a variety of public and private variant databases including the Genome Aggregation Database (gnomAD), Clinical Genomics Database, ClinVar and the Human Gene Mutation Database (HGMD). High-quality data was filtered for rare (≤3 homozygotes in gnomAD) coding variants, intronic variants ±20 bps from the exon-intron boundaries, and clinically-relevant non-coding variants. Testing laboratory: Blueprint Genetics Testing laboratory interpretation: Likely pathogenic
Pathogenic (Nov 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005081134.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36334883) (less)
Pathogenic (Apr 19, 2023)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 71, WITH BEHAVIORAL ABNORMALITIES Affected status: not provided Allele origin: germline	OMIM Accession: SCV003918845.1 First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023	Publications: PubMed (1) PubMed: 36334883 Comment on evidence: In a 21-month-old boy with autosomal dominant intellectual developmental disorder-71 with behavioral abnormalities (MRD71; 620330), Ledger et al. (2023) identified a de novo heterozygous c.3082C-T … (more) In a 21-month-old boy with autosomal dominant intellectual developmental disorder-71 with behavioral abnormalities (MRD71; 620330), Ledger et al. (2023) identified a de novo heterozygous c.3082C-T transition (c.3082C-T, NM_022841.7) in the RFX7 gene, resulting in a pro1028-to-ser (P1028S) substitution at a highly conserved residue. The mutation was found by trio-based whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to be pathogenic. The patient had failure to thrive with microcephaly (-4.17 SD), global developmental delay, speech delay, dyskinetic movements, and oculomotor apraxia. Brain imaging showed progressive ventriculomegaly and white matter loss. (less)

Comment:

This heterozygous missense variant in RFX7 c. 3082C>T, p.(Pro1028Ser) (NM_022841.7) occurred de novo and was predicted to be likely pathogenic. The patient presented with developmental delay, severe failure to thrive, and progressive white matter volume loss.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36334883)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
probably has functional consequence			Medical Genetics Clinic, University of Alberta Accession: SCV002573589.1	Publications PubMed (2)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotype expansion and neurological manifestations of neurobehavioural disease caused by a variant in RFX7.	Ledger ML	European journal of medical genetics	2023	PMID: 36334883
Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.	Harris HK	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33658631
Genomic Analysis of Korean Patient With Microcephaly.	Lee J	Frontiers in genetics	2021	PMID: 33584783

Text-mined citations for this variant ...

Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_022841.7(RFX7):c.3082C>T (p.Pro1028Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...