VCV000158317.55 - ClinVar

NM_017780.4(CHD7):c.7579A>C (p.Met2527Leu)

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.

(18)

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/Likely 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_017780.4(CHD7):c.7579A>C (p.Met2527Leu)

Variation ID: 158317 Accession: VCV000158317.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q12.2 8: 60856859 (GRCh38) [ NCBI UCSC ] 8: 61769418 (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	Nov 23, 2014	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_017780.4:c.7579A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060250.2:p.Met2527Leu	missense
NM_001316690.1:c.1717-5370A>C		intron variant
NC_000008.11:g.60856859A>C
NC_000008.10:g.61769418A>C
NG_007009.1:g.183080A>C
LRG_176:g.183080A>C
LRG_176t1:c.7579A>C	LRG_176p1:p.Met2527Leu
	Q9P2D1:p.Met2527Leu

... more HGVS ... less HGVS

Protein change

M2527L

Other names

NM_017780.3(CHD7):c.7579A>C(p.Met2527Leu)

Canonical SPDI

NC_000008.11:60856858:A:C

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.

0.00040 (C)

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

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

The Genome Aggregation Database (gnomAD), exomes 0.00203

Exome Aggregation Consortium (ExAC) 0.00210

The Genome Aggregation Database (gnomAD) 0.00267

Trans-Omics for Precision Medicine (TOPMed) 0.00280

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00379

Links

ClinGen: CA333506 UniProtKB: Q9P2D1#VAR_068152 dbSNP: rs192129249 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.
CHD7		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3368	3577

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/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jun 22, 2019	RCV000145693.37
CHARGE syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000203938.22
Hypogonadotropic hypogonadism 5 with or without anosmia	Benign (2)	criteria provided, multiple submitters, no conflicts	May 31, 2018	RCV000677330.13
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV001528239.24
Amenorrhea	Uncertain significance (1)	no assertion criteria provided	Mar 8, 2021	RCV001849320.9
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Jun 14, 2017	RCV002312634.9
CHARGE syndrome Hypogonadotropic hypogonadism 5 with or without anosmia	Likely benign (1)	criteria provided, single submitter	Apr 10, 2022	RCV002498662.8
CHD7-related disorder	Benign (1)	no assertion criteria provided	Oct 10, 2019	RCV003891676.2

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.
Benign (Dec 04, 2018)	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: SCV000966271.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (2) PubMed: 21158681‚ 25077900 Comment: The p.Met2527Leu variant in CHD7 is classified as benign because it has been ide ntified in 0.36% (407/113196) of European chromosomes, including 1 homozygous in … (more) The p.Met2527Leu variant in CHD7 is classified as benign because it has been ide ntified in 0.36% (407/113196) of European chromosomes, including 1 homozygous in dividual, by gnomAD (http://gnomad.broadinstitute.org) and due to a lack of cons ervation across species, including mammals. Of note, four mammals have a leucine (Leu) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. Finally, although this variant has been reported in individuals with CHARGE syndrome, it was also identified in their unaffected parents (Bartels 20 10, Marcos 2014). ACMG/AMP Criteria applied: BA1, BP4_Strong, BS4. (less) Number of individuals with the variant: 1
Likely benign (Jun 22, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159208.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020
Benign (Nov 07, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000512584.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is associated with the following publications: (PMID: 27884859, 30921766, 25077900, 21158681, 25996639, 29891883)
Likely benign (Apr 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CHARGE syndrome Hypogonadotropic hypogonadism 5 with or without anosmia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002808887.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004155877.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: CHD7: BS1, BS2 Number of individuals with the variant: 11
Likely benign (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	not specified (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000192801.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Benign (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hypogonadotropic hypogonadism 5 with or without anosmia Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803567.1 First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018	Publications: PubMed (1) PubMed: 25077900 Comment: This variant is interpreted as a Benign, for Hypogonadotropic hypogonadism 5 with or without anosmia, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: … (more) This variant is interpreted as a Benign, for Hypogonadotropic hypogonadism 5 with or without anosmia, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:25077900). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. (less)
Benign (Mar 03, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202473.7 First in ClinVar: Jan 29, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CHD7 Number of individuals with the variant: 1 Sex: mixed
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	CHARGE syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137636.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Kallmann Syndrome 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000474506.3 First in ClinVar: Dec 06, 2016 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 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 (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	CHARGE syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259930.9 First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024
Likely benign (Jun 14, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000847041.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 25077900 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005225795.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921147.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972942.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Benign (Oct 10, 2019)	no assertion criteria provided Method: clinical testing	CHD7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000312999.3 First in ClinVar: Oct 02, 2016 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739634.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (Mar 08, 2021)	no assertion criteria provided Method: literature only	Amenorrhea Affected status: yes Allele origin: unknown	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106785.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 32870266
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Comment:

The p.Met2527Leu variant in CHD7 is classified as benign because it has been ide ntified in 0.36% (407/113196) of European chromosomes, including 1 homozygous in dividual, by gnomAD (http://gnomad.broadinstitute.org) and due to a lack of cons ervation across species, including mammals. Of note, four mammals have a leucine (Leu) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. Finally, although this variant has been reported in individuals with CHARGE syndrome, it was also identified in their unaffected parents (Bartels 20 10, Marcos 2014). ACMG/AMP Criteria applied: BA1, BP4_Strong, BS4.

Comment:

This variant is interpreted as a Benign, for Hypogonadotropic hypogonadism 5 with or without anosmia, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:25077900). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.	Delaney A	The Journal of clinical endocrinology and metabolism	2021	PMID: 32870266
The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.	Marcos S	The Journal of clinical endocrinology and metabolism	2014	PMID: 25077900
Mutations in the CHD7 gene: the experience of a commercial laboratory.	Bartels CF	Genetic testing and molecular biomarkers	2010	PMID: 21158681
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CHD7	-	-	-	-

Text-mined citations for rs192129249 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_017780.4(CHD7):c.7579A>C (p.Met2527Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs192129249 ...