NM_033380.3(COL4A5):c.359G>A (p.Gly120Asp) AND X-linked Alport syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 5, 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:: RCV003994694.2

Allele description [Variation Report for NM_033380.3(COL4A5):c.359G>A (p.Gly120Asp)]

NM_033380.3(COL4A5):c.359G>A (p.Gly120Asp)

Gene:

COL4A5:collagen type IV alpha 5 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.3

Genomic location:

Preferred name:

NM_033380.3(COL4A5):c.359G>A (p.Gly120Asp)

HGVS:

NC_000023.11:g.108568796G>A
NG_011977.2:g.133873G>A
NM_000495.5:c.359G>A
NM_033380.3:c.359G>AMANE SELECT
NP_000486.1:p.Gly120Asp
NP_203699.1:p.Gly120Asp
LRG_232t1:c.359G>A
LRG_232t2:c.359G>A
LRG_232:g.133873G>A
LRG_232p1:p.Gly120Asp
LRG_232p2:p.Gly120Asp
NC_000023.10:g.107812026G>A
NM_033380.2:c.359G>A

Protein change:

G120D

Molecular consequence:

NM_000495.5:c.359G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033380.3:c.359G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked Alport syndrome (ATS1)
Synonyms:: NEPHROPATHY AND DEAFNESS, X-LINKED; Alport syndrome 1, X-linked recessive; Alport Syndrome and Thin Basement Membrane Nephropathy
Identifiers:: MONDO: MONDO:0010520; MedGen: C4746986; Orphanet: 63; Orphanet: 88917; OMIM: 301050

Recent activity

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Arene sp. SWA-2009 voucher MCZ:Mala:378576 28S ribosomal RNA gene, partial seque...
Arene sp. SWA-2009 voucher MCZ:Mala:378576 28S ribosomal RNA gene, partial sequence
gi|290750915|gb|FJ977682.1|

Nucleotide
AGENCOURT_19146027 NICHD_XGC_Te2 Xenopus laevis cDNA clone IMAGE:7208802 5', mRN...
AGENCOURT_19146027 NICHD_XGC_Te2 Xenopus laevis cDNA clone IMAGE:7208802 5', mRNA sequence
gi|43397365|gnl|dbEST|21715851|gb|C 34.1|

Nucleotide
CBXT938.b1 NICHD_XGC_trop_25 Xenopus tropicalis cDNA clone IMAGE:8882853 5', mRN...
CBXT938.b1 NICHD_XGC_trop_25 Xenopus tropicalis cDNA clone IMAGE:8882853 5', mRNA sequence
gi|133817115|gnl|dbEST|45246722|gb| 762.1|

Nucleotide
RecName: Full=Endogenous retrovirus group K member 21 Gag polyprotein; AltName: ...
RecName: Full=Endogenous retrovirus group K member 21 Gag polyprotein; AltName: Full=HERV-K_12q14.1 provirus ancestral Gag polyprotein; Short=Gag polyprotein
gi|50400277|sp|P62683.2|GAK21_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812664	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8218237, 25741868
SCV005086653	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12028435, 14514738, 19965530, 24046192, 35155874, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812664

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005086653

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (6)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Long CG, Braswell E, Zhu D, Apigo J, Baum J, Brodsky B.

Biochemistry. 1993 Nov 2;32(43):11688-95.

PubMed [citation]

PMID:: 8218237

COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome.

Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frascá G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M.

Kidney Int. 2002 Jun;61(6):1947-56.

PubMed [citation]

PMID:: 12028435

See all PubMed Citations (7)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812664.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change in COL4A5 is predicted to replace glycine with aspartic acid at codon 120, p.(Gly120Asp). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments), and alters a critical glycine residue in a collagen triple helix repeat (Gly-X-Y) in the collagenous domain that is a known critical functional domain (PMID: 8218237). There is a moderate physicochemical difference between glycine and aspartic acid. This variant is absent from the population database gnomAD v4.0. To our knowledge, this variant has not been previously reported in the relevant scientific literature. This variant has been identified in an individual with a clinical diagnosis of Alport Syndrome (Royal Melbourne Hospital). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.978). Another missense variant, c.358G>A, p.Gly120Ser, in the same codon with a smaller physicochemical change, has been classified as pathogenic for Alport Syndrome (Shariant). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PM5, PP3_Moderate, 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		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086653.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif within the collagen repeat domain, and affects a glycine residue (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Gly120Ser) has been identified in three individuals with Alport syndrome (PMID: 35155874, VCGS cohort). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: Jul 29, 2024

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