VCV000213921.3 - ClinVar

NM_003242.6(TGFBR2):c.1085A>G (p.His362Arg)

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.

(2)

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(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003242.6(TGFBR2):c.1085A>G (p.His362Arg)

Variation ID: 213921 Accession: VCV000213921.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p24.1 3: 30672268 (GRCh38) [ NCBI UCSC ] 3: 30713760 (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	Oct 11, 2015	Oct 28, 2023	May 20, 2014

HGVS

Nucleotide	Protein	Molecular consequence
NM_003242.6:c.1085A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003233.4:p.His362Arg	missense
NM_001024847.3:c.1160A>G	NP_001020018.1:p.His387Arg	missense
NM_001407126.1:c.1268A>G	NP_001394055.1:p.His423Arg	missense
NM_001407127.1:c.1193A>G	NP_001394056.1:p.His398Arg	missense
NM_001407128.1:c.1112A>G	NP_001394057.1:p.His371Arg	missense
NM_001407129.1:c.1088A>G	NP_001394058.1:p.His363Arg	missense
NM_001407130.1:c.1085A>G	NP_001394059.1:p.His362Arg	missense
NM_001407132.1:c.980A>G	NP_001394061.1:p.His327Arg	missense
NM_001407133.1:c.980A>G	NP_001394062.1:p.His327Arg	missense
NM_001407134.1:c.980A>G	NP_001394063.1:p.His327Arg	missense
NM_001407135.1:c.980A>G	NP_001394064.1:p.His327Arg	missense
NM_001407136.1:c.980A>G	NP_001394065.1:p.His327Arg	missense
NM_001407137.1:c.800A>G	NP_001394066.1:p.His267Arg	missense
NM_001407138.1:c.725A>G	NP_001394067.1:p.His242Arg	missense
NC_000003.12:g.30672268A>G
NC_000003.11:g.30713760A>G
NG_007490.1:g.70767A>G
LRG_779:g.70767A>G
LRG_779t1:c.1160A>G	LRG_779p1:p.His387Arg
LRG_779t2:c.1085A>G	LRG_779p2:p.His362Arg

... more HGVS ... less HGVS

Protein change

H362R, H387R, H327R, H398R, H363R, H423R, H267R, H242R, H371R

Other names

p.H362R:CAC>CGC

Canonical SPDI

NC_000003.12:30672267:A: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.

Links

ClinGen: CA324658 dbSNP: rs863223842 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.
TGFBR2		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1171	1198

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 20, 2014	RCV000200101.2
Loeys-Dietz syndrome 2	Uncertain significance (1)	criteria provided, single submitter	-	RCV003338459.2

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.
Likely pathogenic (May 20, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000250932.11 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: p.His362Arg (CAC>CGC): c.1085 A>G in exon 4 of the TGFBR2 gene (NM_003242.5)The H362R variant in the TGFBR2 gene has not been reported as a disease-causing … (more) p.His362Arg (CAC>CGC): c.1085 A>G in exon 4 of the TGFBR2 gene (NM_003242.5)The H362R variant in the TGFBR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The H362R variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. However, the H362 residue is conserved across species. In silico analysis predicts H362R is probably damaging to the protein structure/function. Mutations in nearby residues (A355P, R356P, G357R, H360P, K372R) have been reported in association with Loeys Dietz, TAAD or related disorders, further supporting the functional importance of this region of the protein. Furthermore, the H362R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. This variant was found in TAAD (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Loeys-Dietz syndrome 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047446.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The c.1085A>G (p.His362Arg) variant has been submitted to ClinVar as a Likely Pathogenic variant, but no details are available for independent assessment. It has not … (more) The c.1085A>G (p.His362Arg) variant has been submitted to ClinVar as a Likely Pathogenic variant, but no details are available for independent assessment. It has not been reported in affected individuals. The p.His362Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid His at position 362 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.His362Arg in TGFBR2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). (less) Clinical Features: Abnormal skeletal morphology (present) , Difficulty walking (present) , Arachnodactyly (present) , Joint laxity (present) , Small thenar eminence (present) , Small hypothenar eminence (present) … (more) Abnormal skeletal morphology (present) , Difficulty walking (present) , Arachnodactyly (present) , Joint laxity (present) , Small thenar eminence (present) , Small hypothenar eminence (present) , Decreased circulating vitamin D concentration (present) , High palate (present) , Low-set ears (present) , Adenoma sebaceum (present) , Pectus carinatum (present) , Dislocated wrist (present) , Kyphoscoliosis (present) , Overlapping toe (present) , Genu valgum (present) , Pes planus (present) , Abnormal intervertebral disk morphology (present) , Abnormal blood phosphate concentration (present) (less)

Comment:

p.His362Arg (CAC>CGC): c.1085 A>G in exon 4 of the TGFBR2 gene (NM_003242.5)The H362R variant in the TGFBR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The H362R variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. However, the H362 residue is conserved across species. In silico analysis predicts H362R is probably damaging to the protein structure/function. Mutations in nearby residues (A355P, R356P, G357R, H360P, K372R) have been reported in association with Loeys Dietz, TAAD or related disorders, further supporting the functional importance of this region of the protein. Furthermore, the H362R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. This variant was found in TAAD

Comment:

The c.1085A>G (p.His362Arg) variant has been submitted to ClinVar as a Likely Pathogenic variant, but no details are available for independent assessment. It has not been reported in affected individuals. The p.His362Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid His at position 362 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.His362Arg in TGFBR2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of 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 rs863223842 ...

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 Apr 06, 2024

ClinVar Genomic variation as it relates to human health

NM_003242.6(TGFBR2):c.1085A>G (p.His362Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs863223842 ...