NM_024596.5(MCPH1):c.1226A>T (p.Glu409Val) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001751293.5

Allele description [Variation Report for NM_024596.5(MCPH1):c.1226A>T (p.Glu409Val)]

NM_024596.5(MCPH1):c.1226A>T (p.Glu409Val)

Gene:

MCPH1:microcephalin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p23.1

Genomic location:

Preferred name:

NM_024596.5(MCPH1):c.1226A>T (p.Glu409Val)

HGVS:

NC_000008.11:g.6444948A>T
NG_016619.2:g.43357A>T
NM_001172574.2:c.1226A>T
NM_001172575.2:c.1082A>T
NM_001322042.1:c.1226A>T
NM_001322042.2:c.1226A>T
NM_001322043.2:c.1220A>T
NM_001322045.2:c.1124A>T
NM_001363979.1:c.1226A>T
NM_001363980.2:c.1226A>T
NM_024596.5:c.1226A>TMANE SELECT
NP_001166045.2:p.Glu409Val
NP_001166046.1:p.Glu361Val
NP_001308971.2:p.Glu409Val
NP_001308972.2:p.Glu407Val
NP_001308974.2:p.Glu375Val
NP_001350908.1:p.Glu409Val
NP_001350909.1:p.Glu409Val
NP_078872.3:p.Glu409Val
NC_000008.10:g.6302469A>T
NC_000008.10:g.6302469A>T
NM_024596.3:c.1226A>T
NR_136159.2:n.1152A>T

Protein change:

E361V

Links:

dbSNP: rs200518541

NCBI 1000 Genomes Browser:

rs200518541

Molecular consequence:

NM_001172574.2:c.1226A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001172575.2:c.1082A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322042.2:c.1226A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322043.2:c.1220A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001322045.2:c.1124A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363979.1:c.1226A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363980.2:c.1226A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024596.5:c.1226A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136159.2:n.1152A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

receptor-type tyrosine-protein phosphatase S isoform X3 [Homo sapiens]
receptor-type tyrosine-protein phosphatase S isoform X3 [Homo sapiens]
gi|2462566611|ref|XP_054177582.1|

Protein
receptor-type tyrosine-protein phosphatase S isoform X20 [Homo sapiens]
receptor-type tyrosine-protein phosphatase S isoform X20 [Homo sapiens]
gi|2462566651|ref|XP_054177602.1|

Protein
PREDICTED: Homo sapiens protein tyrosine phosphatase receptor type S (PTPRS), tr...
PREDICTED: Homo sapiens protein tyrosine phosphatase receptor type S (PTPRS), transcript variant X10, mRNA
gi|2217322239|ref|XM_047439158.1|

Nucleotide
receptor-type tyrosine-protein phosphatase S isoform X16 [Homo sapiens]
receptor-type tyrosine-protein phosphatase S isoform X16 [Homo sapiens]
gi|2462566641|ref|XP_054177597.1|

Protein
PREDICTED: Homo sapiens protein tyrosine phosphatase receptor type S (PTPRS), tr...
PREDICTED: Homo sapiens protein tyrosine phosphatase receptor type S (PTPRS), transcript variant X9, mRNA
gi|2462566614|ref|XM_054321609.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001997244	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 30, 2019)	germline	clinical testing	Citation Link,
SCV002120978	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005195772	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	not provided	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001997244

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Dec 30, 2019)

germline

clinical testing

Citation Link,

SCV002120978

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 16, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005195772

Breakthrough Genomics, Breakthrough Genomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

not provided

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, not provided
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV001997244.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002120978.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 409 of the MCPH1 protein (p.Glu409Val). This variant is present in population databases (rs200518541, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 909149). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Breakthrough Genomics, Breakthrough Genomics, SCV005195772.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 18, 2024

ClinVar

Relating variation to medicine