VCV000547993.17 - ClinVar

NM_052859.4(RFT1):c.1331C>T (p.Thr444Met)

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_052859.4(RFT1):c.1331C>T (p.Thr444Met)

Variation ID: 547993 Accession: VCV000547993.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p21.1 3: 53092496 (GRCh38) [ NCBI UCSC ] 3: 53126512 (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	Jul 9, 2018	May 1, 2024	Sep 27, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_052859.4:c.1331C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_443091.1:p.Thr444Met	missense
NC_000003.12:g.53092496G>A
NC_000003.11:g.53126512G>A
NG_009203.1:g.42959C>T

Protein change

T444M

Other names

Canonical SPDI

NC_000003.12:53092495:G:A

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00037

The Genome Aggregation Database (gnomAD) 0.00039

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

The Genome Aggregation Database (gnomAD), exomes 0.00047

Exome Aggregation Consortium (ExAC) 0.00048

Links

dbSNP: rs147740901 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.
RFT1		-	-	GRCh38 GRCh37	506	557

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.
RFT1-congenital disorder of glycosylation	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Sep 27, 2022	RCV000660602.16
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 4, 2020	RCV001592843.3
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 19, 2021	RCV002530579.2

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 (Sep 08, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RFT1-congenital disorder of glycosylation Affected status: unknown Allele origin: maternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782718.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RFT1-congenital disorder of glycosylation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000897134.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	RFT1-congenital disorder of glycosylation Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001306059.1 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 (Sep 04, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001822340.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Reported in the heterozygous state in a patient with central serous chorioretinopathy who also harbored several variants in other genes (Schellevis et al., 2019); In … (more) Reported in the heterozygous state in a patient with central serous chorioretinopathy who also harbored several variants in other genes (Schellevis et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30724488) (less)
Uncertain significance (Sep 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RFT1-congenital disorder of glycosylation Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000953415.2 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Comment: This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 444 of the RFT1 protein (p.Thr444Met). … (more) This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 444 of the RFT1 protein (p.Thr444Met). This variant is present in population databases (rs147740901, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RFT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547993). 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 RFT1 protein function. 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 (Dec 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RFT1-congenital disorder of glycosylation Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003816121.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jun 19, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003715575.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.1331C>T (p.T444M) alteration is located in exon 12 (coding exon 12) of the RFT1 gene. This alteration results from a C to T substitution … (more) The c.1331C>T (p.T444M) alteration is located in exon 12 (coding exon 12) of the RFT1 gene. This alteration results from a C to T substitution at nucleotide position 1331, causing the threonine (T) at amino acid position 444 to be replaced by a methionine (M). 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:

Reported in the heterozygous state in a patient with central serous chorioretinopathy who also harbored several variants in other genes (Schellevis et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30724488)

Comment:

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 444 of the RFT1 protein (p.Thr444Met). This variant is present in population databases (rs147740901, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RFT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547993). 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 RFT1 protein function. 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 c.1331C>T (p.T444M) alteration is located in exon 12 (coding exon 12) of the RFT1 gene. This alteration results from a C to T substitution at nucleotide position 1331, causing the threonine (T) at amino acid position 444 to be replaced by a methionine (M). 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 rs147740901 ...

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_052859.4(RFT1):c.1331C>T (p.Thr444Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs147740901 ...