VCV002201626.4 - ClinVar

NM_004268.5(MED17):c.727C>T (p.Leu243Phe)

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.

(4)

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_004268.5(MED17):c.727C>T (p.Leu243Phe)

Variation ID: 2201626 Accession: VCV002201626.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q21 11: 93793817 (GRCh38) [ NCBI UCSC ] 11: 93526983 (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	Feb 8, 2023	Nov 24, 2024	May 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004268.5:c.727C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004259.3:p.Leu243Phe	missense
NM_004268.4:c.727C>T
NC_000011.10:g.93793817C>T
NC_000011.9:g.93526983C>T
NG_028028.1:g.14579C>T

... more HGVS ... less HGVS

Protein change

L243F

Other names

p.Leu243Phe

Canonical SPDI

NC_000011.10:93793816: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.

Links

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.
MED17		-	-	GRCh38 GRCh37	523	608

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.
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Dec 6, 2022	RCV002629758.2
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 17, 2024	RCV002644435.3
Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly	Uncertain significance (1)	criteria provided, single submitter	May 20, 2023	RCV004771535.1

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 (Sep 24, 2021)	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: SCV003522961.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces leucine with phenylalanine at codon 243 of the MED17 protein (p.Leu243Phe). The leucine residue is highly conserved and there is a … (more) This sequence change replaces leucine with phenylalanine at codon 243 of the MED17 protein (p.Leu243Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs201499695, ExAC 0.02%). This variant has not been reported in the literature in individuals with MED17-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 06, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003601179.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.727C>T (p.L243F) alteration is located in exon 4 (coding exon 4) of the MED17 gene. This alteration results from a C to T substitution … (more) The c.727C>T (p.L243F) alteration is located in exon 4 (coding exon 4) of the MED17 gene. This alteration results from a C to T substitution at nucleotide position 727, causing the leucine (L) at amino acid position 243 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (May 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005382413.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: The observed missense c.727C>T(p.Leu243Phe) variant in MED17 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. … (more) The observed missense c.727C>T(p.Leu243Phe) variant in MED17 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.01% in gnomAD Exomes database. This variant has been submitted to ClinVar as Uncertain Significance. Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 243 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). (less) Clinical Features: Abnormality of the cardiovascular system (present)
Uncertain significance (May 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005412437.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Number of individuals with the variant: 1

Comment:

This sequence change replaces leucine with phenylalanine at codon 243 of the MED17 protein (p.Leu243Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs201499695, ExAC 0.02%). This variant has not been reported in the literature in individuals with MED17-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.727C>T (p.L243F) alteration is located in exon 4 (coding exon 4) of the MED17 gene. This alteration results from a C to T substitution at nucleotide position 727, causing the leucine (L) at amino acid position 243 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The observed missense c.727C>T(p.Leu243Phe) variant in MED17 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.01% in gnomAD Exomes database. This variant has been submitted to ClinVar as Uncertain Significance. Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 243 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).

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 this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004268.5(MED17):c.727C>T (p.Leu243Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...