VCV000163071.11 - ClinVar

NM_005219.5(DIAPH1):c.2672T>C (p.Ile891Thr)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

3 out of 3 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.2672T>C (p.Ile891Thr)

Variation ID: 163071 Accession: VCV000163071.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q31.3 5: 141529607 (GRCh38) [ NCBI UCSC ] 5: 140909174 (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	Feb 2, 2015	Feb 23, 2026	Feb 11, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_005219.5:c.2672T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005210.3:p.Ile891Thr	missense
NM_001079812.3:c.2645T>C	NP_001073280.1:p.Ile882Thr	missense
NM_001314007.2:c.2672T>C	NP_001300936.1:p.Ile891Thr	missense
NC_000005.10:g.141529607A>G
NC_000005.9:g.140909174A>G
NG_011594.2:g.94449T>C
LRG_1117:g.94449T>C
LRG_1117t1:c.2645T>C	LRG_1117p1:p.Ile882Thr
LRG_1117t2:c.2672T>C	LRG_1117p2:p.Ile891Thr

... more HGVS ... less HGVS

Protein change

I891T, I882T

Other names

Canonical SPDI

NC_000005.10:141529606:A:G

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) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA175659 dbSNP: rs727502961 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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2014	RCV000150402.4
Autosomal dominant nonsyndromic hearing loss 1	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV000269313.5
Autosomal dominant nonsyndromic hearing loss 1 Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	Uncertain significance (1)	criteria provided, single submitter	Feb 11, 2025	RCV003764908.4

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.
Uncertain significance (Jan 12, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Autosomal dominant nonsyndromic hearing loss 1	Illumina Laboratory Services, Illumina Accession: SCV000453365.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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) 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 (Feb 11, 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: SCV004568430.3 First in ClinVar: Feb 28, 2024 Last updated: Feb 23, 2026	Publications: PubMed (1) PubMed: 37086329 Comment: show This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 891 of the DIAPH1 protein (p.Ile891Thr). This variant is present in population databases (rs727502961, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 37086329). ClinVar contains an entry for this variant (Variation ID: 163071). 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

Uncertain significance (Apr 12, 2014) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000197579.4 First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015	Comment: show The Ile891Thr variant in DIAPH1 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analyses do not provide strong support for or a gainst an impact to the protein. In summary, additional information is needed to fully assess its clinical significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

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:

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 891 of the DIAPH1 protein (p.Ile891Thr). This variant is present in population databases (rs727502961, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 37086329). ClinVar contains an entry for this variant (Variation ID: 163071). 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.

Comment:

The Ile891Thr variant in DIAPH1 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analyses do not provide strong support for or a gainst an impact to the protein. In summary, additional information is needed to fully assess its clinical significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome.	Tollefson MR	Human genetics	2023	PMID: 37086329

Text-mined citations for rs727502961 ...

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