NM_002775.5(HTRA1):c.184_185del (p.Cys62fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 1, 2024
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:: RCV002701276.13

Allele description [Variation Report for NM_002775.5(HTRA1):c.184_185del (p.Cys62fs)]

NM_002775.5(HTRA1):c.184_185del (p.Cys62fs)

Gene:

HTRA1:HtrA serine peptidase 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

10q26.13

Genomic location:

Preferred name:

NM_002775.5(HTRA1):c.184_185del (p.Cys62fs)

HGVS:

NC_000010.11:g.122461836_122461837del
NG_011554.1:g.5312_5313del
NM_002775.4:c.184_185del
NM_002775.5:c.184_185delMANE SELECT
NP_002766.1:p.Cys62fs
NC_000010.10:g.124221351_124221352del
NC_000010.10:g.124221352_124221353del
NM_002775.5:c.184_185del

Protein change:

C62fs

Molecular consequence:

NM_002775.5:c.184_185del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens metallothionein 1G (MT1G), transcript variant 2, mRNA
Homo sapiens metallothionein 1G (MT1G), transcript variant 2, mRNA
gi|1677531518|ref|NM_001301267.2|

Nucleotide
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Accession: GDS4069

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002997105	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 29, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19387015, 29895533, 28492532
SCV003924697	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 10, 2023)	germline	clinical testing	Citation Link,
SCV004701800	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002997105

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 29, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003924697

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 10, 2023)

germline

clinical testing

Citation Link,

SCV004701800

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Feb 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.

Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, Kawata H, Koyama A, Arima K, Takahashi T, Ikeda M, Shiota H, Tamura M, Shimoe Y, Hirayama M, Arisato T, Yanagawa S, Tanaka A, Nakano I, Ikeda S, Yoshida Y, Yamamoto T, et al.

N Engl J Med. 2009 Apr 23;360(17):1729-39. doi: 10.1056/NEJMoa0801560.

PubMed [citation]

PMID:: 19387015

Characterization of Heterozygous HTRA1 Mutations in Taiwanese Patients With Cerebral Small Vessel Disease.

Lee YC, Chung CP, Chao NC, Fuh JL, Chang FC, Soong BW, Liao YC.

Stroke. 2018 Jul;49(7):1593-1601. doi: 10.1161/STROKEAHA.118.021283. Epub 2018 Jun 12.

PubMed [citation]

PMID:: 29895533

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002997105.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with HTRA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys62Argfs*106) in the HTRA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HTRA1 are known to be pathogenic (PMID: 19387015, 29895533).

#	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 GeneDx, SCV003924697.1

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

Description

Observed in a patient with cerebral small vessel disease in published literature (Muthusamy et al., 2021); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34510819)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004701800.8

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

Description

HTRA1: PVS1, PM2, PS4:Supporting

#	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		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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