VCV000308887.29 - ClinVar

NM_000376.3(VDR):c.2T>C (p.Met1Thr)

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.

(10)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000376.3(VDR):c.2T>C (p.Met1Thr)

Variation ID: 308887 Accession: VCV000308887.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.11 12: 47879112 (GRCh38) [ NCBI UCSC ] 12: 48272895 (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	Dec 6, 2016	Apr 15, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000376.3:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000367.1:p.Met1Thr	missense initiator codon variant
NM_001017535.2:c.2T>C	NP_001017535.1:p.Met1Thr	missense initiator codon variant
NM_001017536.2:c.152T>C	NP_001017536.1:p.Met51Thr	missense
NM_001364085.2:c.2T>C	NP_001351014.1:p.Met1Thr	missense initiator codon variant
NM_001374661.1:c.2T>C	NP_001361590.1:p.Met1Thr	missense initiator codon variant
NM_001374662.1:c.2T>C	NP_001361591.1:p.Met1Thr	missense initiator codon variant
NC_000012.12:g.47879112A>G
NC_000012.11:g.48272895A>G
NG_008731.1:g.30920T>C

... more HGVS ... less HGVS

Protein change

M1T, M51T

Other names

Canonical SPDI

NC_000012.12:47879111: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.

0.32847 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.62921

Exome Aggregation Consortium (ExAC) 0.63756

Trans-Omics for Precision Medicine (TOPMed) 0.66013

The Genome Aggregation Database (gnomAD) 0.66221

1000 Genomes Project 30x 0.66989

1000 Genomes Project 0.67153

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.67315

Links

ClinGen: CA6534113 dbSNP: rs2228570 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.
VDR		-	-	GRCh38 GRCh37	491	506

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 specified	Benign (3)	criteria provided, single submitter	Feb 17, 2016	RCV000601968.15
Vitamin D-dependent rickets type II with alopecia	Benign (4)	criteria provided, multiple submitters, no conflicts	Dec 5, 2021	RCV000988816.18
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001512350.16
Periodontitis	Benign (1)	no assertion criteria provided	Apr 20, 2023	RCV003992273.1

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.
Benign (Feb 17, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711761.3 First in ClinVar: Apr 09, 2018 Last updated: Sep 03, 2023	Comment: This is a RefSeq error, the reference base (c.152T) is the minor allele. This a llele (T) has been identified in 48% (5540/11550) of Latino … (more) This is a RefSeq error, the reference base (c.152T) is the minor allele. This a llele (T) has been identified in 48% (5540/11550) of Latino chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs22285 70) and thus meets the criteria to be classified as benign. (less) Number of individuals with the variant: 1
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Vitamin D-dependent rickets type II with alopecia Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138701.2 First in ClinVar: Jan 09, 2020 Last updated: Sep 03, 2023
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Vitamin D-dependent rickets type II with alopecia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000378929.4 First in ClinVar: Dec 06, 2016 Last updated: Sep 03, 2023	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Dec 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vitamin D-dependent rickets type II with alopecia Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002514469.2 First in ClinVar: May 21, 2022 Last updated: Sep 03, 2023
Benign (Aug 16, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001950551.3 First in ClinVar: Oct 02, 2021 Last updated: Sep 03, 2023	Comment: This variant is associated with the following publications: (PMID: 16019132, 12807755, 20473893, 18752562, 19131500, 15899948, 21283672, 21814771, 18763633, 9169350, 23855914, 30092343, 27939971, 21820934, 29506625, 22181683, … (more) This variant is associated with the following publications: (PMID: 16019132, 12807755, 20473893, 18752562, 19131500, 15899948, 21283672, 21814771, 18763633, 9169350, 23855914, 30092343, 27939971, 21820934, 29506625, 22181683, 23286944, 24078452, 24702903, 24771013, 27683185) (less)
Benign (Feb 01, 2024)	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: SCV001719750.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741570.4 First in ClinVar: Jul 07, 2021 Last updated: Sep 03, 2023
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958323.2 First in ClinVar: Oct 02, 2021 Last updated: Sep 03, 2023
Benign (Apr 20, 2023)	no assertion criteria provided Method: case-control	periodontitis Affected status: yes Allele origin: germline	Genetics Laboratory, Lanzhou University Accession: SCV004812010.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely pathogenic (Mar 07, 2022)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Vitamin D-dependent rickets type II with alopecia Affected status: yes Allele origin: germline	Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi Accession: SCV002102810.2 First in ClinVar: Mar 12, 2022 Last updated: Sep 03, 2023 Comment: p.(Met1?), missense variant	Publications: PubMed (1) PubMed: 35738466 Number of individuals with the variant: 2 Age: 1-45 years Sex: mixed Geographic origin: India
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This is a RefSeq error, the reference base (c.152T) is the minor allele. This a llele (T) has been identified in 48% (5540/11550) of Latino chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs22285 70) and thus meets the criteria to be classified as benign.

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant is associated with the following publications: (PMID: 16019132, 12807755, 20473893, 18752562, 19131500, 15899948, 21283672, 21814771, 18763633, 9169350, 23855914, 30092343, 27939971, 21820934, 29506625, 22181683, 23286944, 24078452, 24702903, 24771013, 27683185)

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

Title	Author	Journal	Year	Link
Genetic and clinical profile of patients with hypophosphatemic rickets.	Marik B	European journal of medical genetics	2022	PMID: 35738466

Text-mined citations for rs2228570 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000376.3(VDR):c.2T>C (p.Met1Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2228570 ...