VCV000578663.12 - ClinVar

NM_005219.5(DIAPH1):c.3175C>G (p.Leu1059Val)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(1)

2 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005219.5(DIAPH1):c.3175C>G (p.Leu1059Val)

Variation ID: 578663 Accession: VCV000578663.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.3 5: 141527671 (GRCh38) [ NCBI UCSC ] 5: 140907238 (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	Oct 10, 2018	Feb 23, 2026	Jun 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_005219.5:c.3175C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005210.3:p.Leu1059Val	missense
NM_001079812.3:c.3148C>G	NP_001073280.1:p.Leu1050Val	missense
NM_001314007.2:c.3175C>G	NP_001300936.1:p.Leu1059Val	missense
NC_000005.10:g.141527671G>C
NC_000005.9:g.140907238G>C
NG_011594.2:g.96385C>G
LRG_1117:g.96385C>G
LRG_1117t1:c.3148C>G	LRG_1117p1:p.Leu1050Val
LRG_1117t2:c.3175C>G	LRG_1117p2:p.Leu1059Val

... more HGVS ... less HGVS

Protein change

L1059V, L1050V

Other names

Canonical SPDI

NC_000005.10:141527670:G:C

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.

Exome Aggregation Consortium (ExAC) 0.00013

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00010

Links

ClinGen: CA3478844 dbSNP: rs200394036 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.
DIAPH1		-	-	GRCh38 GRCh37	1894	1912

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.
Autosomal dominant nonsyndromic hearing loss 1 Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 29, 2025	RCV000701741.11
not specified	Benign (1)	criteria provided, single submitter	Apr 19, 2021	RCV004017721.1

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.	Expand all rows Collapse all rows 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 (Apr 19, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848550.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: show The p.Leu1059Val variant in DIAPH1 is classified as benign because it has been identified in 0.147% (28/19048) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jun 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Autosomal dominant nonsyndromic hearing loss 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000830555.8 First in ClinVar: Oct 10, 2018 Last updated: Feb 23, 2026	Publications: PubMed (1) PubMed: 28492532 Comment: show This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1059 of the DIAPH1 protein (p.Leu1059Val). This variant is present in population databases (rs200394036, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578663). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1059 of the DIAPH1 protein (p.Leu1059Val). This variant is present in population databases (rs200394036, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578663). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs200394036 ...

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 Mar 01, 2026