NM_005219.5(DIAPH1):c.2108dup (p.Pro704fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 24, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001919847.6

Allele description [Variation Report for NM_005219.5(DIAPH1):c.2108dup (p.Pro704fs)]

NM_005219.5(DIAPH1):c.2108dup (p.Pro704fs)

Gene:

DIAPH1:diaphanous related formin 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

5q31.3

Genomic location:

Preferred name:

NM_005219.5(DIAPH1):c.2108dup (p.Pro704fs)

HGVS:

NC_000005.10:g.141573749dup
NG_011594.2:g.50314dup
NM_001079812.3:c.2081dup
NM_001314007.2:c.2108dup
NM_005219.5:c.2108dupMANE SELECT
NP_001073280.1:p.Pro695fs
NP_001300936.1:p.Pro704fs
NP_005210.3:p.Pro704fs
LRG_1117t1:c.2081dup
LRG_1117t2:c.2108dup
LRG_1117:g.50314dup
LRG_1117p1:p.Pro695fs
LRG_1117p2:p.Pro704fs
NC_000005.9:g.140953308_140953309insG
NC_000005.9:g.140953316dup

Protein change:

P695fs

Links:

dbSNP: rs771360300

NCBI 1000 Genomes Browser:

rs771360300

Molecular consequence:

NM_001079812.3:c.2081dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001314007.2:c.2108dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005219.5:c.2108dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Autosomal dominant nonsyndromic hearing loss 1
Synonyms:: KONIGSMARK SYNDROME; Deafness, autosomal dominant 1; DEAFNESS, AUTOSOMAL DOMINANT 1, WITH OR WITHOUT THROMBOCYTOPENIA
Identifiers:: MONDO: MONDO:0007424; MedGen: C1852282; Orphanet: 90635; OMIM: 124900

Name:: Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Synonyms:: Seizures, cortical blindness, and microcephaly syndrome
Identifiers:: MONDO: MONDO:0014714; MedGen: C5567650; OMIM: 616632

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002160944	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24781755, 26463574, 33176815, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002160944

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.

Ercan-Sencicek AG, Jambi S, Franjic D, Nishimura S, Li M, El-Fishawy P, Morgan TM, Sanders SJ, Bilguvar K, Suri M, Johnson MH, Gupta AR, Yuksel Z, Mane S, Grigorenko E, Picciotto M, Alberts AS, Gunel M, Šestan N, State MW.

Eur J Hum Genet. 2015 Feb;23(2):165-72. doi: 10.1038/ejhg.2014.82. Epub 2014 Apr 30.

PubMed [citation]

PMID:: 24781755
PMCID:: PMC4297910

Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures.

Al-Maawali A, Barry BJ, Rajab A, El-Quessny M, Seman A, Coury SN, Barkovich AJ, Yang E, Walsh CA, Mochida GH, Stoler JM.

Am J Med Genet A. 2016 Feb;170A(2):435-440. doi: 10.1002/ajmg.a.37422. Epub 2015 Oct 13.

PubMed [citation]

PMID:: 26463574
PMCID:: PMC5315085

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002160944.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Pro704Thrfs*71) in the DIAPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DIAPH1 are known to be pathogenic (PMID: 24781755, 26463574). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive DIAPH1-related conditions (PMID: 33176815). ClinVar contains an entry for this variant (Variation ID: 1395984). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Apr 20, 2025

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