VCV000958620.33 - ClinVar

NM_002382.5(MAX):c.179G>A (p.Arg60Gln)

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.

(3)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002382.5(MAX):c.179G>A (p.Arg60Gln)

Variation ID: 958620 Accession: VCV000958620.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q23.3 14: 65078029 (GRCh38) [ NCBI UCSC ] 14: 65544747 (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	Jul 16, 2020	Mar 10, 2024	Feb 11, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_002382.5:c.179G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002373.3:p.Arg60Gln	missense
NM_001271069.2:c.144+15679G>A		intron variant
NM_001320415.2:c.-96G>A		5 prime UTR
NM_001407094.1:c.179G>A	NP_001394023.1:p.Arg60Gln	missense
NM_001407095.1:c.152G>A	NP_001394024.1:p.Arg51Gln	missense
NM_001407096.1:c.179G>A	NP_001394025.1:p.Arg60Gln	missense
NM_001407097.1:c.179G>A	NP_001394026.1:p.Arg60Gln	missense
NM_001407098.1:c.71G>A	NP_001394027.1:p.Arg24Gln	missense
NM_001407099.1:c.152G>A	NP_001394028.1:p.Arg51Gln	missense
NM_001407100.1:c.152G>A	NP_001394029.1:p.Arg51Gln	missense
NM_001407101.1:c.152G>A	NP_001394030.1:p.Arg51Gln	missense
NM_001407102.1:c.152G>A	NP_001394031.1:p.Arg51Gln	missense
NM_001407103.1:c.179G>A	NP_001394032.1:p.Arg60Gln	missense
NM_001407104.1:c.179G>A	NP_001394033.1:p.Arg60Gln	missense
NM_001407105.1:c.-96G>A
NM_001407106.1:c.-96G>A
NM_001407107.1:c.-96G>A
NM_001407108.1:c.152G>A	NP_001394037.1:p.Arg51Gln	missense
NM_001407109.1:c.152G>A	NP_001394038.1:p.Arg51Gln	missense
NM_001407110.1:c.152G>A	NP_001394039.1:p.Arg51Gln	missense
NM_001407111.1:c.-189G>A
NM_001407112.1:c.-189G>A
NM_145112.3:c.152G>A	NP_660087.1:p.Arg51Gln	missense
NM_145113.3:c.179G>A	NP_660088.1:p.Arg60Gln	missense
NM_197957.4:c.171+15679G>A		intron variant
NR_073137.2:n.303G>A
NR_176275.1:n.321G>A
NR_176278.1:n.152G>A
NR_176279.1:n.255G>A
NR_176280.1:n.321G>A
NR_176281.1:n.321G>A
NR_176282.1:n.125G>A
NC_000014.9:g.65078029C>T
NC_000014.8:g.65544747C>T
NG_029830.1:g.29481G>A
LRG_530:g.29481G>A
LRG_530t1:c.179G>A	LRG_530p1:p.Arg60Gln

... more HGVS ... less HGVS

Protein change

R51Q, R60Q, R24Q

Other names

Canonical SPDI

NC_000014.9:65078028:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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

COSMIC: 166665 OMIM: 154950.0006 dbSNP: rs2063106020 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.
MAX		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	404	551

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.
Hereditary pheochromocytoma-paraganglioma	Uncertain significance (1)	criteria provided, single submitter	Feb 11, 2022	RCV001231817.7
Polydactyly-macrocephaly syndrome	Pathogenic (1)	no assertion criteria provided	Feb 8, 2024	RCV003595722.2
MAX-associated Macrocephaly and Polydactyly syndrome	Pathogenic (1)	no assertion criteria provided	Oct 18, 2022	RCV003222266.1

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 (Feb 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary pheochromocytoma-paraganglioma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001404349.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 27903915 Comment: This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is … (more) This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 60 of the MAX protein (p.Arg60Gln). This variant has not been reported in the literature in individuals affected with MAX-related conditions. ClinVar contains an entry for this variant (Variation ID: 958620). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MAX function (PMID: 27903915). 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)
Pathogenic (Oct 18, 2022)	no assertion criteria provided Method: clinical testing	MAX-associated Macrocephaly and Polydactyly syndrome Affected status: yes Allele origin: de novo	Molecular Medicine, University of Leeds Accession: SCV002584947.1 First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023	Number of individuals with the variant: 3 Age: 0-10 years Sex: male Ethnicity/Population group: European Caucasoid Geographic origin: Europe
Pathogenic (Feb 08, 2024)	no assertion criteria provided Method: literature only	POLYDACTYLY-MACROCEPHALY SYNDROME Affected status: not provided Allele origin: unknown	OMIM Accession: SCV004363649.2 First in ClinVar: Feb 14, 2024 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 38141607 Comment on evidence: In 3 unrelated children with polydactyly-macrocephaly syndrome (PDMCS; 620712), Harris et al. (2024) identified heterozygosity for the same de novo c.179G-A transition (c.179G-A, NM_002382.5) in … (more) In 3 unrelated children with polydactyly-macrocephaly syndrome (PDMCS; 620712), Harris et al. (2024) identified heterozygosity for the same de novo c.179G-A transition (c.179G-A, NM_002382.5) in exon 4 of the MAX gene, resulting in an arg60-to-gln (R60Q) substitution at a highly conserved residue within the bHLHZ domain. The variant was not present in the dbSNP (build 153) or gnomAD databases, but had been identified 56 times as a somatic mutation in tumor tissue in the COSMIC database. Analysis of transfected HEK293 cells revealed increased transcription and protein levels of CCND2 (123833) with the mutant compared to wildtype MAX. Further analysis demonstrated that the bHLHZ domain of the R60Q mutant disfavored the formation of the repressive homodimeric E-box complex, and partitioned as a heterodimer and specific activating DNA complex with c-Myc (MYC; 190080) more readily than wildtype MAX, likely increasing transcriptional activity. RNA-seq analysis showed broad transcriptional dysregulation in the presence of the R60Q mutant compared to wildtype MAX. (less)

Comment:

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 60 of the MAX protein (p.Arg60Gln). This variant has not been reported in the literature in individuals affected with MAX-related conditions. ClinVar contains an entry for this variant (Variation ID: 958620). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MAX function (PMID: 27903915). 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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Molecular Medicine, University of Leeds Accession: SCV002584947.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.	Harris EL	American journal of human genetics	2024	PMID: 38141607
MAX is an epigenetic sensor of 5-carboxylcytosine and is altered in multiple myeloma.	Wang D	Nucleic acids research	2017	PMID: 27903915

Text-mined citations for rs2063106020 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002382.5(MAX):c.179G>A (p.Arg60Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2063106020 ...