VCV000194122.26 - ClinVar

NM_024596.5(MCPH1):c.2180C>T (p.Pro727Leu)

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.

(9)

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
Uncertain significance(7); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024596.5(MCPH1):c.2180C>T (p.Pro727Leu)

Variation ID: 194122 Accession: VCV000194122.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p23.1 8: 6499895 (GRCh38) [ NCBI UCSC ] 8: 6357416 (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	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001118887.2:c.*3206G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_024596.5:c.2180C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078872.3:p.Pro727Leu	missense
NM_001118888.2:c.*3206G>A		3 prime UTR
NM_001147.3:c.*3206G>A		3 prime UTR
NM_001322042.2:c.2180C>T	NP_001308971.2:p.Pro727Leu	missense
NM_001363979.1:c.2180C>T	NP_001350908.1:p.Pro727Leu	missense
NM_001363980.2:c.1935+44643C>T		intron variant
NM_001386335.1:c.*3206G>A		3 prime UTR
NM_001386336.1:c.*3354G>A		3 prime UTR
NM_001386337.1:c.*3354G>A		3 prime UTR
NM_001410916.1:c.2180C>T	NP_001397845.1:p.Pro727Leu	missense
NM_001410917.1:c.2180C>T	NP_001397846.1:p.Pro727Leu	missense
NC_000008.11:g.6499895C>T
NC_000008.10:g.6357416C>T
NG_016619.2:g.98304C>T
NG_016619.3:g.98270C>T
NG_029483.1:g.68369G>A

... more HGVS ... less HGVS

Protein change

P727L

Other names

Canonical SPDI

NC_000008.11:6499894: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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00083

The Genome Aggregation Database (gnomAD) 0.00086

Trans-Omics for Precision Medicine (TOPMed) 0.00094

The Genome Aggregation Database (gnomAD), exomes 0.00099

Exome Aggregation Consortium (ExAC) 0.00108

Links

ClinGen: CA239944 dbSNP: rs199861426 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.
ANGPT2		-	-	GRCh38 GRCh37	-	238
MCPH1		-	-	GRCh38 GRCh38 GRCh38 GRCh37	811	1244

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.
Microcephaly 1, primary, autosomal recessive	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 16, 2021	RCV000270996.7
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Dec 1, 2023	RCV000656854.24
Intellectual disability Short stature	Uncertain significance (1)	criteria provided, single submitter	Apr 19, 2019	RCV001270063.2
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Apr 21, 2022	RCV004020067.1

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 (Jul 06, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614065.2 First in ClinVar: Dec 06, 2016 Last updated: Oct 19, 2018
Uncertain significance (Nov 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly 1, primary, autosomal recessive Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002793568.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 05, 2022)	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: SCV002274571.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 32714618 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the MCPH1 protein (p.Pro727Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the MCPH1 protein (p.Pro727Leu). This variant is present in population databases (rs199861426, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary microcephaly (PMID: 32714618). ClinVar contains an entry for this variant (Variation ID: 194122). 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 expected to disrupt MCPH1 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)
Likely benign (Apr 21, 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: SCV004904822.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 32714618 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)
Uncertain significance (Apr 18, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225701.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MCPH1 Number of individuals with the variant: 3 Sex: mixed
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Microcephaly 1, primary, autosomal recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000474627.3 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, 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 (Apr 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Short stature Intellectual disability Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448818.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Intellectual disability (present) , Short stature (present) , Failure to thrive (present) , Delayed speech and language development (present) Sex: male
Uncertain significance (Jul 14, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329415.7 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in twin females with primary … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in twin females with primary microcephaly in the published literature, but a second variant in the MCPH1 gene was not reported in these patients (Pavone et al., 2020); This variant is associated with the following publications: (PMID: 31101089, 32714618) (less)
Likely benign (Dec 01, 2023)	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: SCV004159481.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: MCPH1: BS1 Number of individuals with the variant: 2

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 727 of the MCPH1 protein (p.Pro727Leu). This variant is present in population databases (rs199861426, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary microcephaly (PMID: 32714618). ClinVar contains an entry for this variant (Variation ID: 194122). 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 expected to disrupt MCPH1 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:

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.

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:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in twin females with primary microcephaly in the published literature, but a second variant in the MCPH1 gene was not reported in these patients (Pavone et al., 2020); This variant is associated with the following publications: (PMID: 31101089, 32714618)

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
Primary Microcephaly with Novel Variant of MCPH1 Gene in Twins: Both Manifesting in Childhood at the Same Time with Hashimoto's Thyroiditis.	Pavone P	Journal of pediatric genetics	2020	PMID: 32714618
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MCPH1	-	-	-	-

Text-mined citations for rs199861426 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_024596.5(MCPH1):c.2180C>T (p.Pro727Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199861426 ...